Process of making cftr modulators

ABSTRACT

The disclosure provides processes for synthesizing Compound I, and pharmaceutically acceptable salts thereof.

This application claims priority from U.S. Provisional Application No.62/886,660, filed Aug. 14, 2019, which is hereby incorporated byreference in its entirety.

Disclosed herein are processes for making a modulator of cystic fibrosistransmembrane conductance regulator (“CFTR”).

Cystic fibrosis (CF) is a recessive genetic disease that affectsapproximately 70,000 children and adults worldwide. Despite progress inthe treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed inrespiratory epithelia lead to reduced apical anion secretion, causing animbalance in ion and fluid transport. The resulting decrease in aniontransport contributes to enhanced mucus accumulation in the lung andaccompanying microbial infections that ultimately cause death in CFpatients. In addition to respiratory disease, CF patients typicallysuffer from gastrointestinal problems and pancreatic insufficiency that,if left untreated, result in death. In addition, the majority of maleswith CF are infertile, and fertility is reduced among females with CF.

Sequence analysis of the CFTR gene has revealed a variety ofdisease-causing mutations (Cutting, G. R. et al. (1990) Nature346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. etal. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl.Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations inthe CF gene have been identified; currently, the CFTR2 database containsinformation on 412 of these identified mutations, with sufficientevidence to define 346 mutations as disease-causing. The most prevalentdisease-causing mutation is a deletion of phenylalanine at position 508of the CFTR amino acid sequence and is commonly referred to as the ΔF508mutation. This mutation occurs in most of the cases of cystic fibrosisand is associated with severe disease.

The deletion of residue 508 in CFTR prevents the nascent protein fromfolding correctly. This results in the inability of the mutant proteinto exit the endoplasmic reticulum (ER) and traffic to the plasmamembrane. As a result, the number of CFTR channels for anion transportpresent in the membrane is far less than observed in cells expressingwild-type CFTR, i.e., CFTR having no mutations. In addition to impairedtrafficking, the mutation results in defective channel gating. Together,the reduced number of channels in the membrane and the defective gatinglead to reduced anion and fluid transport across epithelia. (Quinton, P.M. (1990), FASEB J. 4: 2709-2727). The channels that are defectivebecause of the ΔF508 mutation are still functional, albeit lessfunctional than wild-type CFTR channels. (Dalemans et al. (1991), NatureLond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50). In addition to ΔF508, other disease-causing mutations in CFTRthat result in defective trafficking, synthesis, and/or channel gatingcould be up-regulated or down-regulated to alter anion secretion andmodify disease progression and/or severity.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a varietyof cell types, including absorptive and secretory epithelial cells,where it regulates anion flux across the membrane, as well as theactivity of other ion channels and proteins. In epithelial cells, normalfunctioning of CFTR is critical for the maintenance of electrolytetransport throughout the body, including respiratory and digestivetissue. CFTR is composed of approximately 1480 amino acids that encode aprotein which is made up of a tandem repeat of transmembrane domains,each containing six transmembrane helices and a nucleotide bindingdomain. The two transmembrane domains are linked by a large, polar,regulatory (R)-domain with multiple phosphorylation sites that regulatechannel activity and cellular trafficking.

Chloride transport takes place by the coordinated activity of ENaC andCFTR present on the apical membrane and the Na⁺—K⁺-ATPase pump and Cl⁻channels expressed on the basolateral surface of the cell. Secondaryactive transport of chloride from the luminal side leads to theaccumulation of intracellular chloride, which can then passively leavethe cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump, and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I):

also known as(14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione,is disclosed in PCT Application No. PCT/US2019/018042, which isincorporated herein by reference in its entirety, as a modulator of CFTRactivity and thus useful in treating CFTR-mediated diseases such as CF.There remains, however, a need for efficient processes for the synthesisof Compound I that delivers this compound or pharmaceutically acceptablesalts thereof, for example, in higher yield, with higher selectivity, orwith higher purity relative to known processes.

Disclosed herein are processes for making(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I):

and pharmaceutically acceptable salts thereof.

Definitions

As used herein, “CFTR” means cystic fibrosis transmembrane conductanceregulator.

As used herein, the terms “treatment,” “treating,” and the likegenerally mean the improvement of CF or its symptoms, or lessening theseverity of CF or its symptoms, or a delay in the onset of CF or itssymptoms, in a subject. “Treatment,” as used herein, includes, but isnot limited to, the following: increased growth of the subject,increased weight gain, reduction of mucus in the lungs, improvedpancreatic and/or liver function, reduction of chest infections, and/orreductions in coughing or shortness of breath. Improvements in orlessening the severity of any of these symptoms can be readily assessedaccording to standard methods and techniques known in the art.

The terms “patient” and “subject” are used interchangeably and refer toan animal, including humans.

As used herein, “mutations” can refer to mutations in the CFTR gene orthe CFTR protein. A “CFTR gene mutation” refers to a mutation in theCFTR gene, and a “CFTR protein mutation” refers to a mutation in theCFTR protein. In general, a genetic defect or mutation, or a change inthe nucleotides in a gene results in a mutation in the CFTR proteintranslated from that gene, or a frame shift(s).

The term “ΔF508” refers to a mutant CFTR protein which is lacking theamino acid phenylalanine at position 508.

As used herein, the term “modulator” refers to a compound that increasesthe activity of a biological compound or molecule such as a protein. Forexample, a CFTR modulator is a compound that increases the activity ofCFTR. The increase in activity resulting from a CFTR modulator includes,but is not limited to, compounds that correct, potentiate, stabilize,and/or amplify CFTR.

As used herein, the term “amorphous” refers to a solid material havingno long-range order in the position of its molecules. Amorphous solidsare generally supercooled liquids in which the molecules are arranged ina random manner so that there is no well-defined arrangement, e.g.,molecular packing, and no long-range order. Amorphous solids aregenerally isotropic, i.e., exhibit similar properties in all directionsand do not have definite melting points. For example, an amorphousmaterial is a solid material having no sharp characteristic crystallinepeak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is notcrystalline as determined by XRPD). Instead, one or several broad peaks(e.g., halos) appear in its XRPD pattern. Broad peaks are characteristicof an amorphous solid. See US 2004/0006237 for a comparison of XRPDs ofan amorphous material and a crystalline material.

As used herein, the term “substantially amorphous” refers to a solidmaterial having little or no long-range order in the position of itsmolecules. For example, substantially amorphous materials have less than15% crystallinity (e.g., less than 10% crystallinity or less than 5%crystallinity). It is also noted that the term “substantially amorphous”includes the descriptor “amorphous,” which refers to materials having no(0%) crystallinity.

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein.

The term “chemically stable,” as used herein, means that the solid formof Compound I does not decompose into one or more different chemicalcompounds when subjected to specified conditions, e.g., 40° C./75%relative humidity, for a specific period of time, e.g., 1 day, 2 days, 3days, 1 week, 2 weeks, or longer. In some embodiments, less than 25% ofthe solid form of Compound I decomposes. In some embodiments, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,less than about 3%, less than about 1%, less than about 0.5% of the formof Compound I decomposes under the conditions specified. In someembodiments, no detectable amount of the solid form of Compound Idecomposes.

The term “physically stable,” as used herein, means that the solid formof Compound I does not change into one or more different physical formsof Compound I (e.g., different solid forms as measured by XRPD, DSC,etc.) when subjected to specific conditions, e.g., 40° C./75% relativehumidity, for a specific period of time, e.g, 1 day, 2 days, 3 days, 1week, 2 weeks, or longer. In some embodiments, less than 25% of thesolid form of Compound I changes into one or more different physicalforms when subjected to specified conditions. In some embodiments, lessthan about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 3%, less than about 1%, less than about 0.5%of the solid form of Compound I changes into one or more differentphysical forms of Compound I when subjected to specified conditions. Insome embodiments, no detectable amount of the solid form of Compound Ichanges into one or more physically different solid forms of Compound I.

As used herein, the terms “about” and “approximately,” when used inconnection with amounts, volumes, reaction times, reaction temperatures,etc. mean an acceptable error for a particular value as determined byone of ordinary skill in the art, which depends in part on how the valueis measured or determined. In certain embodiments, the term “about” or“approximately” means within 1, 2, 3, or 4 standard deviations. Incertain embodiments, the term “about” or “approximately” means within30%,25%,20%,15%,10%,9%, 8%,7%, 6%,5%, 4%, 3%, 2%,1%,0.5%, 0.1%, or 0.05%of a given value or range.

The term “compound,” when referring to a compound of this disclosure,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules.

Compounds described herein may optionally be substituted with one ormore substituents, such as are illustrated generally above, or asexemplified by particular classes, subclasses, and species of thedisclosure. It will be appreciated that the phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted.” In general, the term “substituted,” whether preceded bythe term “optionally” or not, indicates that at least one hydrogen ofthe “substituted” group is replaced with a substituent. Unless otherwiseindicated, an “optionally substituted” group may have a suitablesubstituent at each substitutable position of the group, and when morethan one position in any given structure may be substituted with morethan one substituent chosen from a specified group, the substituent maybe either the same or different at each position. Combinations ofsubstituents envisioned by this disclosure are preferably those thatresult in the formation of stable or chemically feasible compounds.

The term “stable compounds,” as used herein, refers to compounds whichpossess sufficient stability to allow for their manufacture and whichmaintain the integrity of the compounds for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediates, and/or treating adisease or condition responsive to therapeutic agents).

The term “aliphatic” or “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched) or branched, substituted, orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic,” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃₋₈ hydrocarbon or bicyclic or tricyclic C₈₋₁₄hydrocarbon that is completely saturated or that contains one or moreunits of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitable aliphaticgroups include, but are not limited to, linear or branched, substitutedor unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof,such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl.Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl(e.g., decalin), bridged bicycloalkyl such as norbomyl or[2.2.2]bicyclo-octyl, and bridged tricyclic such as adamantyl.

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “alkyl group” refers to a saturated, branched,or unbranched aliphatic hydrocarbon containing carbon atoms (such as,for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, or 20 carbon atoms). Alkyl groups may be substituted orunsubstituted.

As used herein, the term “haloalkyl group” refers to an alkyl groupsubstituted with one or more halogen atoms.

The term “halogen” or “halo” means F, Cl, Br, or I.

As used herein, “cycloalkyl group” refers to a cyclic, non-aromatichydrocarbon group containing 3-12 carbons in a ring (such as, forexample, 3-10 carbons). Cycloalkyl groups encompass monocyclic,bicyclic, tricyclic, bridged, fused, and spiro rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl,spiro[2.2]pentane, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may besubstituted or unsubstituted.

The term “heteroaliphatic,” as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced with one ormore heteroatoms, for example, oxygen, sulfur, nitrogen, phosphorus, orsilicon. Heteroaliphatic groups may be substituted or unsubstituted,branched or unbranched, cyclic or acyclic, and include “heterocycle,”“heterocyclyl,” “heterocycloaliphatic,” and “heterocyclic” groups.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including any oxidized form of nitrogen, sulfur,phosphorus, or silicon; the quaternized form of any basic nitrogen; anda substitutable nitrogen of a heterocyclic ring, for example, N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl)).

The term “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or“heterocyclic” as used herein means non-aromatic monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members is anindependently chosen heteroatom. In some embodiments, the “heterocycle,”“heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic” group hasthree to fourteen ring members in which one or more ring members is aheteroatom independently chosen from oxygen, sulfur, nitrogen, andphosphorus, and each ring in the system contains three to seven ringmembers.

The terms “haloaliphatic” and “haloalkoxy” means aliphatic or alkoxy, asthe case may be, substituted with one or more halo atoms. Examples ofhaloaliphatic include —CHF₂, —CH₂F, —CF₃, —CF₂—, and perhaloalkyl, suchas —CF₂CF₃.

The term “alkoxy group” as used herein refers to an alkyl or cycloalkylgroup covalently bonded to an oxygen atom. Alkoxy groups may besubstituted or unsubstituted and branched or unbranched.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains three to seven ring members.The term “aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains three to seven ring members.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may be optionally substituted with one or more substituents.

The term “protecting group,” as used herein, refers to any chemicalgroup introduced into a molecule by chemical modification of afunctional group in order to obtain chemoselectivity in a subsequentchemical reaction.

Methods of adding (a process generally referred to as “protecting”) andremoving (process generally referred to as “deprotecting”) protectinggroups are well-known in the art and available, for example, in P. J.Kocienski, Protecting Groups, 3^(rd) edition (Thieme, 2005), and inGreene and Wuts, Protective Groups in Organic Synthesis, 4th edition(John Wiley & Sons, New York, 2007), both of which are herebyincorporated by reference in their entirety.

Non-limiting examples of useful protecting groups for amines that may beused in this disclosure include monovalent protecting groups, forexample, t-butyloxycarbonyl (Boc), benzyl (Bn), β-methoxyethoxytrityl(MEM), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts); and divalent protecting groups,for example, benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

Non-limiting examples of useful protecting groups for alcohols that maybe used in this disclosure include, for example, acetyl (Ac), benzoyl(Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT),methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB),pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS).

Non-limiting examples of useful protecting groups for carboxylic acidsthat may be used in this disclosure include, for example, methyl orethyl esters, substituted alkyl esters such as 9-fluorenylmethyl,methoxymethyl (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP),tetrahydrofuranyl, β-methoxyethoxymethyl (MEM),2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM),pivaloyloxymethyl (POM), phenylacetoxymethyl, and cyanomethyl, acetyl(Ac), phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl,cyclohexyl, allyl, methallyl, cinnamyl, phenyl (Ph), silyl esters,benzyl and substituted benzyl esters, 2,6-dialkylphenyl, andpentafluorophenyl (PFP).

Non-limiting examples of suitable solvents that may be used in thisdisclosure include, for example, water (H₂O), methanol (MeOH), methylenechloride or dichloromethane (DCM; CH₂Cl₂), acetonitrile (MeCN; CH₃CN),N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate(MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butylacetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF),2-methyl tetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK),tert-butanol, diethyl ether (Et₂O), methyl tert-butyl ether (MTBE),1,4-dioxane, and N-methylpyrrolidone (NMP).

Non-limiting examples of amine bases that may be used in this disclosureinclude, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N-methylmorpholine (NMM), triethylamine (Et₃N; TEA), diisopropylethylamine (i-Pr₂EtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine,7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), and potassium bis(trimethylsilyl)amide (KHMDS). In someembodiments, the amine base is in IPA.

Non-limiting examples of carbonate bases that may be used in thisdisclosure include, for example, sodium carbonate (Na₂CO₃), potassiumcarbonate (K₂CO₃), cesium carbonate (Cs₂CO₃), lithium carbonate(Li₂CO₃), sodium bicarbonate (NaHCO₃), and potassium bicarbonate(KHCO₃).

Non-limiting examples of alkoxide bases that may be used in thisdisclosure include, for example, t-AmOLi (lithium t-amylate), t-AmONa(sodium t-amylate), t-AmOK (potassium

t-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide(KOtBu), and sodium methoxide (NaOMe; NaOCH₃). In some embodiments, thealkoxide base is in THF. In some embodiments, the alkoxide base is in2-MeTHF. In some embodiments, the alkoxide base is in IPA.

Non-limiting examples of hydroxide bases that may be used in thisdisclosure include, for example, sodium hydroxide (NaOH), potassiumhydroxide (KOH), and lithium hydroxide (LiOH). In some embodiments, thehydroxide base is in THF. In some embodiments, the hydroxide base is in2-MeTHF. In some embodiments, the hydroxide base is in IPA.

Non-limiting examples of phosphate bases that may be used in thisdisclosure include, for example, sodium phosphate tribasic (Na₃PO₄),potassium phosphate tribasic (K₃PO₄), potassium phosphate dibasic(K₂HPO₄), and potassium phosphate monobasic (KH₂PO₄).

Non-limiting examples of suitable sulfonate esters —OSO₂R that may beused in this disclosure include, for example, methanesulfonyl (R=Me),p-toluenesulfonyl (R=4-MeC₆H₄—), and 4-nitrobenzylsulfonyl(R=4-NO₂C₆H₄—).

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric forms of the structure, e.g., geometric (orconformational), such as (Z) and (E) double bond isomers, and (Z) and(E) conformational isomers. Therefore, geometric and conformationalmixtures of the compounds of the disclosure are within the scope of thedisclosure.

Unless otherwise stated, all tautomeric forms of the compounds of thedisclosure are within the scope of the disclosure.

“Stereoisomer” refers to both enantiomers and diastereomers.

“Tert” and “t-” are used interchangeably and mean tertiary.

The disclosure also provides processes for preparing salts of thecompounds of the disclosure.

A salt of a compound of this disclosure is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. In some embodiments, the salt is a pharmaceutically acceptablesalt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response, and the like, and iscommensurate with a reasonable benefit/risk ratio.

A “pharmaceutically acceptable salt” means any non-toxic salt that, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound of this disclosure. A “pharmaceuticallyacceptable counterion” is an ionic portion of a salt that is not toxicwhen released from the salt upon administration to a recipient. One ofordinary skill in the art would recognize that, when an amount of “acompound or a pharmaceutically acceptable salt thereof” is disclosed,the amount of the pharmaceutically acceptable salt form of the compoundis the amount equivalent to the concentration of the free base of thecompound. It is noted that the disclosed amounts of the compounds ortheir pharmaceutically acceptable salts thereof herein are based upontheir free base form. For example, “10 mg of at least one compoundchosen from Compound I and pharmaceutically acceptable salts thereof”includes 10 mg of Compound I and a concentration of a pharmaceuticallyacceptable salt of Compound I equivalent to 10 mg of Compound I.

Suitable pharmaceutically acceptable salts are, for example, thosedisclosed in S. M. Berge, et al. J. Pharm. Sci., 1977, 66, 1-19. Forexample, Table 1 of that article provides the following pharmaceuticallyacceptable salts:

TABLE 1 Pharmaceutically Acceptable Salts Acetate BenzenesulfonateBenzoate Bicarbonate Bitartrate Bromide Calcium edetate CamsylateCarbonate Chloride Citrate Dihydrochloride Edetate Edisylate EstolateEsylate Fumarate Gluceptate Gluconate Glutamate GlycollylarsanilateHexylresorcinate Hydrabamine Hydrobromide HydrochlorideHydroxynaphthoate Iodide Isethionate Lactate Lactobionate Malate MaleateMandelate Mesylate Methylbromide Methylnitrate Methylsulfate MucateNapsylate Nitrate Pamoate (Embonate) Pantothenate Phosphate/diphosphatePolygalacturonate Salicylate Stearate Subacetate Succinate SulfateTannate Tartrate Teociate Triethiodide Benzathine Chloroprocaine CholineDiethanolamine Ethylenediamine Meglumine Procaine Aluminum CalciumLithium Magnesium Potassium Sodium Zinc

Non-limiting examples of pharmaceutically acceptable salts derived fromappropriate acids include: salts formed with inorganic acids, such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid; salts formed with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid; and salts formed by using other methods used in the art,such as ion exchange. Non-limiting examples of pharmaceuticallyacceptable salts include adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphorsulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.Non-limiting examples of pharmaceutically acceptable salts derived fromappropriate bases include alkali metal, alkaline earth metal, ammonium,and N⁺(C₁₋₄alkyl)₄ salts. This disclosure also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Suitable non-limiting examples of alkali and alkalineearth metal salts include sodium, lithium, potassium, calcium, andmagnesium. Further non-limiting examples of pharmaceutically acceptablesalts include ammonium, quaternary ammonium, and amine cations formedusing counterions, such as halide, hydroxide, carboxylate, sulfate,phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Othersuitable, non-limiting examples of pharmaceutically acceptable saltsinclude besylate and glucosamine salts.

In the compounds of this disclosure, any atom not specificallydesignated as a particular isotope is meant to represent any stableisotope of that atom. Unless otherwise stated, when a position isdesignated specifically as “H” or “hydrogen,” the position is understoodto have hydrogen at its natural abundance isotopic composition.

The term “derivative” as used herein refers to a collection of moleculeshaving a chemical structure identical to a compound of this disclosure,except that one or more atoms of the molecule may have been substitutedwith another atom. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C or ¹⁴C are within the scope of this disclosure. Such compounds areuseful as, for example, analytical tools, probes in biological assays,or compounds with improved therapeutic profiles.

In some embodiments, the derivative is a silicon derivative, in which atleast one carbon atom in a disclosed compound has been replaced withsilicon. In some embodiments, the at least one carbon atom replaced withsilicon may be a non-aromatic carbon. In some embodiments, the at leastone carbon atom replaced with silicon may be an aromatic carbon. Incertain embodiments, the silicon derivatives of the invention may alsohave one or more hydrogen atoms replaced with deuterium and/orgermanium.

In other embodiments, the derivative is a germanium derivative, in whichat least one carbon atom in a disclosed compound has been replaced withgermanium. In certain embodiments, the germanium derivatives of theinvention may also have one or more hydrogen atoms replaced withdeuterium and/or silicon.

Because the general properties of silicon and germanium are similar tothose of carbon, replacement of carbon by silicon or germanium canresult in compounds with similar biological activity to acarbon-containing original compound.

The disclosure provides a method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (I):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof, wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(c) is selected from F, Cl, Br, and I.

In some embodiments, X^(a) is Br and X^(c) is F.

In some embodiments, the conversion of the compound of Formula (I), or asalt thereof, into Compound I, or a pharmaceutically acceptable saltthereof, comprises the steps of:

1) combining the compound of Formula (I), or a salt thereof, with atleast one first base to produce a compound of Formula (II):

or a salt thereof; and

2) combining the compound of Formula (II), or a salt thereof, withcompound 1:

or a salt thereof, and at least one second base to produce Compound I,or a pharmaceutically acceptable salt thereof, wherein in the compoundof Formula (II), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.

In some embodiments, in the compound of Formula (II), or a salt thereof,X^(a) is Br.

In some embodiments, the at least one first base is selected fromcarbonate bases, hydroxide bases, alkoxide bases, acetate bases, aminebases, phosphate bases, and sulfate bases. In some embodiments, the atleast one first base is selected from sodium carbonate (Na₂CO₃),potassium carbonate (K₂CO₃), 2,2,6,6-tetramethylpiperidine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO₃), and potassiumphosphate tribasic (K₃PO₄).

In some embodiments, the combination of the compound of Formula (II), ora salt thereof, with compound 1, or a salt thereof, comprises at leastone metal catalyst. In some embodiments, the at least one metal catalystis selected from palladium catalysts and copper catalysts.

In some embodiments, the palladium catalyst is selected from[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3),[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,5′-triphenyl-1′H-[1,4′]bipyrazole,Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(Pd₂dba₃/BrettPhos),Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (XPhos Pd G3),dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)(Pd(BINAP)Cl₂), Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether(Pd₂dba₃/DPEPhos),Pd₂dba₃/1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,Pd₂dba₃/2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃(tert-butyl XPhos/Pd₂dba₃),[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)chloride (tBuXPhos-Pd-G1),allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (t-BuBrettPhos-Pd-G3),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃(t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonateallyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate/Pd₂dba₃(SPhos/Pd₂dba₃),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂),[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)(Pd(dtbpf)Cl₂),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPSIIpent),di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃(cBRIDP/Pd₂dba₃), and1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane/Pd₂dba₃(Cy-cBRIDP/Pd₂dba₃). The active catalyst, palladium (0)2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) can be generated using palladium (II) tBuXPhosprecatalyst (G1-G3) or a combination of a palladium (0) source, forexample Pd₂(dba)₃ or Pd(PPh₃)₄, anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) and finally by using palladium (II) source, such asPd(OAc)₂ or Pd(Cl)₂ in the presence of a reducing agent anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos).

In some embodiments, the copper catalyst is selected from copper(II)fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper (I)thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluenecomplex, optionally substituted with a ligand such asN,N-dimethylethylenediamine, N,N-dimethylcyclohexane-1,2-diamine),1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid,2,2′-bipyridine, 2-acetylcyclohexanone,1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane,2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol,(1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime,glycolic acid, L-proline, 2,2′-dipyridyl, andN-cyclohexyl-2,6-bis(1-methylethyl)benzenamine. In some embodiments, thecopper catalyst is optionally substituted with a ligand selected fromN,N-diisopropyl-1,3-propanediamine

trans-1,2-diaminocyclohexane

N,N′-dimethyl-1,3-propanediamine

N,N′-diethylethane-1,2-diamine

3-(dimethylamino)-propylamine

1,4-diaminocyclohexane

N,N′-dimethylethane-1,2-diamine

diethylenetriamine

and trans-N,N-dimethylcyclohexane-1,2-diamine

In some embodiments, the at least one metal catalyst is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0)(Pd₂dba₃), copper iodide (CuI), or a combination thereof.

In some embodiments, step 2) further comprises excess2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos)relative to[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3). In some embodiments, the at least onesecond base is a carbonate base, such as potassium carbonate (K₂CO₃) orcesium carbonate (Cs₂CO₃).

In some embodiments, the conversion of the compound of Formula (I), or asalt thereof, into Compound I, or a pharmaceutically acceptable saltthereof, comprises the steps of combining the compound of Formula (I),or a salt thereof, with compound 1:

or a salt thereof, and at least one third base to produce Compound I, ora pharmaceutically acceptable salt thereof,wherein in the compound of Formula (I), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(c) is selected from F, Cl, Br, and I.

In some embodiments, in the compound of Formula (I), or a salt thereof,X^(a) is Br and X^(c) is F.

In some embodiments, the at least one third base is selected fromcarbonate bases, hydroxide bases, alkoxide bases, acetate bases, aminebases, phosphate bases, and sulfate bases. In some embodiments, the atleast one third base is selected from sodium carbonate (Na₂CO₃),potassium carbonate (K₂CO₃), 2,2,6,6-tetramethylpiperidine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO₃), and potassiumphospahate (K₃PO₄).

In some embodiments, the combination of the compound of Formula (II), ora salt thereof, with compound 1, or a salt thereof, further comprises atleast one metal catalyst. In some embodiments, the at least one metalcatalyst is selected from palladium catalysts and copper catalysts.

In some embodiments, the palladium catalyst is selected from[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3),[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,5′-triphenyl-1′H-[1,4′]bipyrazole,Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(Pd₂dba₃/BrettPhos),Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (XPhos Pd G3),dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)(Pd(BINAP)Cl₂), Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether(Pd₂dba₃/DPEPhos),Pd₂dba₃/1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,Pd₂dba₃/2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃(tert-Butyl XPhos/Pd₂dba₃),[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)chloride (tBuXPhos-Pd-G1),allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (t-BuBrettPhos-Pd-G3),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃(t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonateallyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate/Pd₂dba₃(SPhos/Pd₂dba₃),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)(Pd(dtbpf)Cl₂),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPSIIpent),di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃(cBRIDP/Pd₂dba₃), and1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane/Pd₂dba₃(Cy-cBRIDP/Pd₂dba₃). The active catalyst, palladium (0)2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) can be generated using palladium (II) tBuXPhosprecatalyst (G1-G3) or a combination of a palladium (0) source, forexample Pd₂(dba)₃ or Pd(PPh₃)₄, anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) and finally by using palladium (II) source, such asPd(OAc)₂ or Pd(Cl)₂ in the presence of a reducing agent anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos).

In some embodiments, the copper catalyst is selected from copper(II)fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I)thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluenecomplex, optionally substituted with a ligand such asN,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine),1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid,2,2′-bipyridine, 2-acetylcyclohexanone,1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane,2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol,(1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime,glycolic acid, L-proline, 2,2′-dipyridyl, andN-cyclohexyl-2,6-bis(1-methylethyl)benzeneamine. In some embodiments,the copper catalyst is optionally substituted with a ligand selectedfrom N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane,N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine,3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane,N,N′-dimethylethane-1,2-diamine, diethylenetriamine, andtrans-N,N-dimethylcyclohexane-1,2-diamine.

In some embodiments, the at least one metal catalyst is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0)(Pd₂dba₃), copper iodide (CuI), or a combination thereof.

In some embodiments, the compound of Formula (I):

or a salt thereof, is prepared by converting a compound of Formula(III):

or a salt thereof, into the compound of Formula (I), or a salt thereof,wherein in the compound of Formula (III), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro;

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (III), or a saltthereof, X^(a) is Br, X^(c) is F, and R¹ and R², together with the atomsto which they are attached, form N-phthalimide.

In some embodiments, the conversion of the compound of Formula (III), ora salt thereof, into the compound of Formula (I), or a salt thereof,comprises the steps of:

1) combining the compound of Formula (III), or a salt thereof, in thepresence of water and a base selected from lithium hydroxide (LiOH),hydrazine, ethanolamine, and N-methylamine; and

2) optionally combining the product of step 1) with an acid selectedfrom oxalic acid, hydrochloric acid (HCl), phosphoric acid (H₃PO₄), andcitric acid; then treating the reaction mixture with water and a baseselected from potassium carbonate (K₂CO₃) and cesium carbonate (Cs₂CO₃)to produce the compound of Formula (I), or a salt thereof.

In some embodiments, the compound of Formula (III):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (III), or a saltthereof,wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro;

X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

In some embodiments, R¹ and R², together with the atoms to which theyare attached, form a nitrogen protecting group selected frombenzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (IV), or a salt thereof,X^(a) is Br, and R¹ and R², together with the atoms to which they areattached, form N-phthalimide. In some embodiments, in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, R¹ is hydrogen, and R² isbenzyloxycarbonyl (Cbz).

In some embodiments, in the compound of Formula (V), or a salt thereof,X^(b) is —OC₆F₅ and X^(c) is F. In some embodiments, the amide of thecompound of Formula (IV), or the amide of a salt thereof, is protectedwith a nitrogen protecting group.

In some embodiments, the combination of the compound of Formula (IV), ora salt thereof, with the compound of Formula (V), or a salt thereof, isperformed in the presence of at least one fourth base. In someembodiments, the at least one fourth base is an alkoxy base. In someembodiments, the alkoxy base is selected from lithium t-amylate(t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), andlithium t-butoxide (LiOt-Bu).

In some embodiments, the compound of Formula (IV):

or a salt thereof, is prepared by converting a compound of Formula (VI):

or a salt thereof, into the compound of Formula (IV), or a salt thereof,wherein in the compound of Formula (VI), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.

In some embodiments, the amide of the compound of Formula (IV), or theamide of a salt thereof, is protected with a nitrogen protecting group.

In some embodiments, in the compound of Formula (VI), or a salt thereof,X^(a) is Br.

In some embodiments, the conversion of the compound of Formula (VI), ora salt thereof, into the compound of Formula (IV), or a salt thereof,comprises the steps of:

1) converting the hydroxy group of the compound of formula (VI), or asalt thereof, into a sulfonate ester (—OSO₂R) or Cl; and

2) combining the sulfonate ester or Cl of step 1) with an amine and atleast one fifth base to produce the compound of Formula (IV), or a saltthereof.

In some embodiments, the R group of the sulfonate ester (—OSO₂R) isselected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionallysubstituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro. In someembodiments, the conversion of the hydroxy group into a sulfonate esterin step 1) is performed in the presence of methanesulfonyl chloride(MsCl) and triethylamine (TEA). In some embodiments, the amine in step2) is N-phthalimide and the at least one fifth base in step 2) is acarbonate base, such as potassium carbonate (K₂CO₃) or cesium carbonate(Cs₂CO₃).

In some embodiments, the compound of Formula (VI):

or a salt thereof, is prepared by combining compound 2:

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (VI), or a saltthereof,wherein in the compound of Formula (VII), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(d) is selected from F, Cl, Br, and I.

In some embodiments, in the compound of Formula (VII), or a saltthereof, X^(a) is Br and X^(d) is F.

In some embodiments, the combination of compound 2, or a salt thereof,with the compound of Formula (VII), or a salt thereof, is performed inthe presence of at least one sixth base. In some embodiments, the atleast one sixth base is selected from potassium t-butoxide (KOt-Bu),lithium hydroxide (LiOH), potassium phosphate tribasic (K₃PO₄),potassium phosphate dibasic (K₂HPO₄), cesium carbonate (Cs₂CO₃),2,2,6,6-tetramethylpiperidine,7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),triethylamine (TEA), tributylamine (Bu₃N), sodium bicarbonate (NaHCO₃),potassium bicarbonate (KHCO₃), sodium carbonate (Na₂CO₃) and potassiumcarbonate (K₂CO₃). In some embodiments, the combination of compound 2,or a salt thereof, with the compound of Formula (VII), or a saltthereof, is performed in the presence of potassium carbonate (K₂CO₃) inan aqueous solution in a substrate in 2-MeTHF.

In some embodiments, compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.

In some embodiments, the conversion of compound 3, or a salt thereof,into compound 2, or a salt thereof, is performed in the presence of areducing agent. In some embodiments, the reducing agent is selected fromlithium aluminum hydride (LiAlH₄), sodium bis(2-methoxyethoxy)aluminumhydride, borane (BH₃), and borane-tetrahydrofuran (BH₃-THF).

In some embodiments, compound 3:

or a salt thereof, is prepared by converting compound 4:

or a salt thereof, into compound 3, or a salt thereof.

In some embodiments, the conversion of compound 4, or a salt thereof,into compound 3, or a salt thereof, is performed in the presence ofreducing reaction conditions. In some embodiments, the reducing reactionconditions comprise hydrogen gas (H₂) and at least one metal catalystselected from Raney Nickel (Ra—Ni), palladium on carbon (Pd/C),palladium on alumina (Pd/Al₂O₃), palladium(II) chloride (PdCl₂),platinum oxide (PtO₂), palladium/platinum on carbon (Pd/Pt/C), platinumon carbon (Pt/C), and nickel(II) chloride/sodium borohydride(NiCl₂/NaBH₄).

In some embodiments, compound 4:

or a salt thereof, is prepared by chiral resolution of compound (±)-4:

or a salt thereof.

In some embodiments, the chiral resolution of compound (±)-4, or a saltthereof, is performed using a method selected from chiral columnchromatography, chiral Simulated Moving Bed (SMB), bioresolution,enzymatic resolution, liquid chromatography, salt resolution, andasymmetric hydrogenation.

The disclosure provides a method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (VIII):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof, wherein in the compound of Formula (VIII), or a saltthereof, X^(c) is selected from F, Cl, Br, and I.

In some embodiments, the conversion of the compound of Formula (VIII),or a salt thereof, into Compound I, or a pharmaceutically salt thereof,is performed in the presence of at least one seventh base. In someembodiments, the at least one seventh base is selected from potassiumcarbonate (K₂CO₃), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,1,3,3-tetramethylguanidine, potassium hydroxide (KOH),potassium hydroxide/Triton B (KOH/Triton B), potassiumhydroxide//tetra-n-butylammonium iodide (KOH/nBu₄NH₄I), potassiumhydroxide/tetra-n-octylammonium bromide (KOH/n-Oct₄NH₄Br), lithiumhydroxide (LiOH), and lithium carbonate (Li₂CO₃). In some embodiments,the conversion of the compound of Formula (VIII), or a salt thereof,into Compound I, or a pharmaceutically salt thereof, further comprisesmagnesium chloride (MgCl₂).

In some embodiments, the compound of Formula (VIII):

or a salt thereof, is prepared by converting a compound of Formula (IX):

or a salt thereof, into the compound of Formula (VIII), or a saltthereof,wherein in the compound of Formula (IX), or a salt thereof:

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (IX), or a salt thereof,X is F, R¹ is hydrogen, and R² is benzyloxycarbonyl (Cbz).

In some embodiments, the conversion of the compound of Formula (IX), ora salt thereof, into the compound of Formula (VIII), or a salt thereof,is performed in the presence of reducing reaction conditions. In someembodiments, the reducing reaction conditions are selected from hydrogengas (H₂) and palladium on carbon (Pd/C), HCO₂H/Et₃N/Pd(C), NH₄HCO₂/K₂CO₃and palladium on carbon, K₂HPO₄ and Pd/C, K₃PO₄ and Pd/C, NH₂NH₂/Pd(C),and 1,4-cyclohexadiene/Pd(C).

In some embodiments, the compound of Formula (IX):

or a salt thereof, is prepared by combining a compound of Formula (X):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (IX), or a saltthereof,wherein in the compound of Formula (X), or a salt thereof:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and

wherein in the compound of Formula (V), or a salt thereof:

X^(b) is selected from Cl, F, —OC₆F₅,

and

X^(c) is selected from F, Cl, Br, and I.

In some embodiments of the compound of Formula (V) or a salt thereof,X^(b) is

and the salt is the ⁻OTf salt.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (X), or a salt thereof,R¹ is hydrogen and R² is Cbz, or R¹ and R², together with the atoms towhich they are attached, form N-phthalimide.

In some embodiments, in the compound of Formula (V), or a salt thereof,X^(b) is —OC₆F₅ and X^(c) is F.

In some embodiments, the combination of the compound of Formula (X), ora salt thereof, with the compound of Formula (V), or a salt thereof, isperformed in the presence of at least one eighth base. In someembodiments, the at least one eighth base is an alkoxy base. In someembodiments, the alkoxy base is selected from lithium t-amylate(t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), andlithium t-butoxide (LiOt-Bu).

In some embodiments, the compound of Formula (X):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with compound 1:

or a salt thereof, to produce the compound of Formula (X), or a saltthereof,wherein in the compound of Formula (IV), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with        —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro; and        wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (IV), or a salt thereof,X^(a) is Br, and R¹ and R², together with the atoms to which they areattached, form N-phthalimide. In some embodiments, in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, R¹ is hydrogen, and R² isbenzyloxycarbonyl (Cbz).

In some embodiments, the amide of the compound of Formula (IV), or theamide of a salt thereof, is protected with a nitrogen protecting group.

In some embodiments, the combination of the compound of Formula (IV), ora salt thereof, with compound 1, or a salt thereof, is performed in thepresence of at least one ninth base. In some embodiments, the at leastone ninth base is selected from carbonate bases, hydroxide bases,alkoxide bases, acetate bases, amine bases, phosphate bases, and sulfatebases. In some embodiments, the at least one ninth base is selected fromsodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), cesium carbonate(Cs₂CO₃), lithium carbonate (Li₂CO₃), sodium hydroxide (NaOH), potassiumhydroxide (KOH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide(KOt-Bu), pyridine, 2,2,6,6-tetramethylpiperidine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, N,N-diisopropylethylamine (DIPEA), potassiumbis(trimethylsilyl)amide (KHMDS), pyridine, sodium bicarbonate (NaHCO₃),potassium bicarbonate (KHCO₃), sodium phosphate tribasic (Na₃PO₄), andpotassium phosphate tribasic (K₃PO₄). In some embodiments, the at leastone ninth base is in THF. In some embodiments, the at least one ninthbase is in 2-MeTHF. In some embodiments, the at least one ninth base isin IPA.

In some embodiments, the combination of the compound of Formula (II), ora salt thereof, with compound 1, or a salt thereof, further comprises atleast one metal catalyst. In some embodiments, the at least one metalcatalyst is selected from palladium catalysts and copper catalysts. Insome embodiments, the palladium catalyst is selected from[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3),[1,1′-bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,5′-triphenyl-1′H-[1,4′]bipyrazole,Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(Pd₂dba₃/BrettPhos),Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (XPhos Pd G3),dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)(Pd(BINAP)Cl₂), Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether(Pd₂dba₃/DPEPhos),Pd₂dba₃/1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,Pd₂dba₃/2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃(tert-Butyl XPhos/Pd₂dba₃);[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)chloride (tBuXPhos-Pd-G1),allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (t-BuBrettPhos-Pd-G3),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃(t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonateallyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate/Pd₂dba₃(SPhos/Pd₂dba₃), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl₂,[1,1′-b(di-tert-butylphosphino)ferrocene] dichloropalladium(II)(Pd(dtbpf)Cl₂),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPSIIpent),di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃(cBRIDP/Pd₂dba₃), and1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane/Pd₂dba₃(Cy-cBRIDP/Pd₂dba₃). The active catalyst, palladium (0)2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) can be generated using palladium (II) tBuXPhosprecatalyst (G1-G3) or a combination of a palladium (0) source, forexample Pd₂(dba)₃ or Pd(PPh₃)₄, anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) and finally by using palladium (II) source, such asPd(OAc)₂ or Pd(Cl)₂ in the presence of a reducing agent anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos).

In some embodiments, the copper catalyst is selected from copper(II)fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I)thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluenecomplex, optionally substituted with a ligand such asN,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine),1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid,2,2′-bipyridine, 2-acetylcyclohexanone,1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane,2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol,(1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime,glycolic acid, L-proline, 2,2′-dipyridyl, andN-cyclohexyl-2,6-bis(1-methylethyl)benzenamine. In some embodiments, thecopper catalyst is optionally substituted with a ligand selected fromN,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane,N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine,3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane,N,N′-dimethylethane-1,2-diamine, diethylenetriamine, andtrans-N,N-dimethylcyclohexane-1,2-diamine.

In some embodiments, the at least one metal catalyst is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0)(Pd₂dba₃), copper iodide (CuI), or a combination thereof. In someembodiments, combining a compound of Formula of (IV), or a salt thereof,with compound 1, or a salt thereof, further comprises copper iodide(CuI).

In some embodiments, the combination of the compound of Formula (IV), ora salt thereof, with compound 1, or a salt thereof, further comprisesdicyclohexylamine (DMCHDA). In some embodiments, the at least one ninthbase is potassium carbonate (K₂CO₃).

In some embodiments, the compound of Formula (IV):

or a salt thereof, is prepared by combining a compound of Formula (XI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (IV), or a saltthereof,wherein in the compound of Formula (XI), or a salt thereof:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and wherein in the compound of Formula (VII),or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(d) is selected from F, Cl, Br, and I.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

In some embodiments, in the compound of Formula (XI), or a salt thereof,R¹ is hydrogen and R² is benzyloxycarbonyl (Cbz). In some embodiments,in the compound of Formula (XI), or a salt thereof, R¹ and R², togetherwith the atoms to which they are attached, form N-phthalimide.

In some embodiments, in the compound of Formula (VII), or a saltthereof, X^(a) is Br and X^(d) is F.

In some embodiments, the amide of the compound of Formula (IV), or theamide of a salt thereof, is protected with a nitrogen protecting group.

In some embodiments, the combination of the compound of Formula (XI), ora salt thereof, with the compound of Formula (VII), or a salt thereof,is performed in the presence of at least one tenth base. In someembodiments, the at least one tenth base is selected from amine bases,carbonate bases, hydroxide bases, and phosphate bases. In someembodiments, the at least one tenth base is potassium carbonate (K₂CO₃).In some embodiments, the combination of the compound of Formula (XI), ora salt thereof, with the compound of Formula (VII), or a salt thereof,further comprises zinc chloride (ZnCl₂), magnesium chloride (MgCl₂),aluminum oxide (Al₂O₃), cesium fluoride (CsF), indium(III) triflate(In(OTf)₃), or indium(III) chloride (InCl₃). In some embodiments, thecombination of the compound of Formula (XI), or a salt thereof, with thecompound of Formula (VII), or a salt thereof, further comprises zincchloride (ZnCl₂).

In some embodiments, the compound of Formula (XI):

or a salt thereof, is prepared by converting a compound of Formula(XII):

or a salt thereof, into the compound of Formula (XI), or a salt thereof,wherein in the compound of Formula (XII), or a salt thereof, R³ is amonovalent nitrogen protecting group. In some embodiments, eachmonovalent nitrogen protecting group is selected from t-butyloxycarbonyl(Boc), benzyloxycarbonyl (Cbz), and N-phthalimide. In some embodiments,in the compound of Formula (XII), or a salt thereof, R³ ist-butyloxycarbonyl (Boc).

In some embodiments, the conversion of the compound of Formula (XII), ora salt thereof, into the compound of Formula (XI), or a salt thereof,comprises the steps of:

1) converting the primary amine of the compound of Formula (XII), or asalt thereof, into a protected amine —NR¹R²; and

2) deprotecting R³ to produce the compound of Formula (XI), or a saltthereof.

In some embodiments, the conversion in step 1) is performed in thepresence of benzyl chloroformate (Cbz-Cl) and potassium carbonate (KOH).In some embodiments, R³ in step 2) is deprotected with hydrochloric acid(HCl), methanesulfonic acid (MsOH), or trifluoroacetic acid.

In some embodiments, the compound of Formula (XII):

or a salt thereof, is prepared by converting the compound of Formula(XV):

or a salt thereof, into the compound of Formula (XII), or a saltthereof,wherein in the compound of Formula (XV), or a salt thereof, R³ is amonovalent nitrogen protecting group. In some embodiments, eachmonovalent nitrogen protecting group is independently selected fromt-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts). In some embodiments, in the compound of Formula (XV), or a saltthereof, R³ is t-butyloxycarbonyl (Boc).

In some embodiments, the conversion of the compound of Formula (XV), ora salt thereof, into the compound of Formula (XII), or a salt thereof,comprises the steps of:

1) converting the compound of Formula (XV):

or a salt thereof, into the compound of Formula (XIV):

or a salt thereof;

2) converting the compound of Formula (XIV), or a salt thereof, into thecompound of Formula (XIII):

or a salt thereof; and

3) converting the compound of Formula (XIII), or a salt thereof, intothe compound of Formula (XII), or a salt thereof,

wherein in the compounds of Formulae (XIII)-(XV), or salts thereof, R³is a monovalent nitrogen protecting group; andwherein in the compound of Formula (XIV), or a salt thereof:

R⁴ is —SO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, in thecompounds of Formulae (XIII)-(XV), or salts thereof, R³ ist-butyloxycarbonyl (Boc). In some embodiments, in the compound ofFormula (XIV), or a salt thereof, R⁴ is 4-nitrobenzylsulfonyl (Ns).

In some embodiments, step 1) of the conversion of the compound ofFormula (XV), or a salt thereof, into the compound of Formula (XII), ora salt thereof, is performed in the presence of 4-nitrobenzylsulfonylchloride (NsCl) and at least one eleventh base. In some embodiments, theat least one eleventh base is an amine base or a carbonate base. In someembodiments, the at least one eleventh base is triethylamine (Et₃N),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N,N-diisopropylethylamine((iPr)₂NEt). In some embodiments, step 2) of the conversion of thecompound of Formula (XV), or a salt thereof, into the compound ofFormula (XII), or a salt thereof, is performed in the presence of anazide source. In some embodiments, the azide source is sodium azide(NaN₃). In some embodiments, step 3) of the conversion of the compoundof Formula (XV), or a salt thereof, into the compound of Formula (XII),or a salt thereof, is performed in the presence of reducing reactionconditions. In some embodiments, the reducing reaction conditionscomprise hydrogen gas (H₂) and platinum dioxide (PtO₂) or palladium oncarbon (Pd/C).

In some embodiments, the compound of Formula (XV):

or a salt thereof, is prepared by converting compound 2:

or a salt thereof, into the compound of Formula (XV), or a salt thereof.

In some embodiments, the conversion of compound 2, or a salt thereof,into the compound of Formula (XV), or a salt thereof, is performed inthe presence of di-tert-butyl dicarbonate (Boc₂O). In some embodiments,the compound of Formula (XV), or a salt thereof, is treated withL-glutamic acid.

In some embodiments, compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.

In some embodiments, the conversion of compound 3, or a salt thereof,into compound 2, or a salt thereof, is performed in the presence of areducing agent. In some embodiments, the reducing agent is selected fromlithium aluminum hydride (LiAlH₄), sodium bis(2-methoxyethoxy)aluminumhydride, borane (BH₃), and borane-tetrahydrofuran (BH₃-THF). In someembodiments, the solvent is 2-methyltetrahydrofuran (2-MeTHF) ortetrahydrofuran (THF).

In some embodiments, compound 3:

or a salt thereof, is prepared by chiral resolution of compound (±)-3:

or a salt thereof.

In some embodiments, the chiral resolution of compound (±)-3, or a saltthereof, is performed using a method selected from chiral columnchromatography, chiral Simulated Moving Bed (SMB), bioresolution,enzymatic resolution, liquid chromatography, salt resolution, andasymmetric hydrogenation.

In some embodiments, compound (±)-3:

or a salt thereof, is prepared by converting compound (±)-4:

or a salt thereof, into compound (±)-3, or a salt thereof.

In some embodiments, the conversion of compound (±)-4, or a saltthereof, into compound (±)-3, or a salt thereof, is performed in thepresence of reducing reaction conditions.

In some embodiments, the reducing reaction conditions comprise hydrogengas (H₂) and Raney Nickel.

In some embodiments, compound (±)-4:

or a salt thereof, is prepared by combining compound 5:

or a salt thereof, with 2-nitropropane to produce compound (±)-4, or asalt thereof.

In some embodiments, the combination of compound 5, or a salt thereof,with 2-nitropropane is performed in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In some embodiments, compound 5:

or a salt thereof, is prepared by converting δ-valerolactone intocompound 5, or a salt thereof.

In some embodiments, the conversion of δ-valerolactone into compound 5,or a salt thereof, comprises the steps of:

1) combining δ-valerolactone with an alkyl formate and at least onetwelfth base; and

2) combining the product of step 1) with paraformaldehyde.

In some embodiments, the method further comprises contacting the productof step 2) with SiO₂ to produce compound 5, or a salt thereof. In someembodiments, the alkyl formate is ethyl formate and the at least onetwelfth base is sodium hydride (NaH).

In some embodiments, compound 1:

or a salt thereof, is prepared by converting compound 6:

or a salt thereof, into compound 1, or a salt thereof. In someembodiments, the conversion of compound 6, or a salt thereof, intocompound 1, or a salt thereof, is performed in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In some embodiments, compound 6:

or a salt thereof, is prepared by converting compound 7:

or a salt thereof, into compound 6, or a salt thereof.

In some embodiments, the conversion of compound 7, or a salt thereof,into compound 6, or a salt thereof, is performed in the presence of atleast one thirteenth base and at least one solvent. In some embodiments,the at least one thirteenth base is potassium hydroxide (KOH). In someembodiments, the at least one solvent is methanol (MeOH).

In some embodiments, compound 7:

or a salt thereof, is prepared by combining compound 8:

or a salt thereof, with compound 9:

or a salt thereof, to produce compound 7, or a salt thereof.

In some embodiments, the combination of compound 8, or a salt thereof,with compound 9, or a salt thereof, is performed in the presence of aphosphine and an azodicarboxylate. In some embodiments, the phosphine istriphenylphosphine (PPh₃). In some embodiments, the azodicarboxylate isdiisopropyl azocarboxylate (DIAD). In some embodiments, the combinationof compound 8, or a salt thereof, with compound 9, or a salt thereof, isperformed in the presence of a sulfonyl chloride and at least onefourteenth base. In some embodiments, the sulfonyl chloride ismethanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl). Insome embodiments, the at least one fourteenth base is triethylamine(Et₃N).

In some embodiments, compound 8:

or a salt thereof, is prepared by converting compound 10:

or a salt thereof, into compound 8, or a salt thereof.

In some embodiments, the conversion of compound 10, or a salt thereof,into compound 8, or a salt thereof, is performed in the presence of areducing agent. In some embodiments, the reducing agent is selected fromlithium aluminum hydride (LiAlH₄), boron trifluoride/sodium borohydride(BF₃/NaBH₄), borane (BH₃) and borane complexes such as boranedimethylsulfide (BH₃SMe₂) and borane-tetrahydrofuran (BH₃-THF), Vitride(sodium bis(2-methoxyethoxy)aluminium hydride), zinc borohydride(Zn(BH₄)₂), and diisobutylalum-inui hydride (DIBAL-H).

In some embodiments, compound 10:

or a salt thereof, is prepared by converting compound 11:

or a salt thereof, into compound 10, or a salt thereof.

In some embodiments, the conversion of compound 11, or a salt thereof,into compound 10, or a salt thereof, is performed in the presence of atleast one fifteenth base and at least one solvent. In some embodiments,the at least one fifteenth base is selected from sodium hydroxide(NaOH), potassium hydroxide (KOH), and barium hydroxide (Ba(OH)₂). Insome embodiments, the at least one solvent is selected from ethanol(EtOH), methanol (MeOH), ethylene glycol, diethylene glycol, and water.In an alternate embodiment the conversion of compound 11, or a saltthereof, into compound 10, or a salt thereof, is performed in acidichydrolysis conditions, such as hydrochloric acid (HCl), hydrobromic acid(HBr), sulfuric acid (H₂SO₄), phosphoric acid (H₃PO₄) in water, andacetic acid (HOAc). In an alternative embodiment, the conversion ofcompound 11, or a salt thereof, into compound 10, or a salt thereof, isperformed in the presence of a nitrilase enzyme.

In some embodiments, compound 11:

or a salt thereof, is prepared by converting compound 12:

or a salt thereof, into compound 11, or a salt thereof.

In some embodiments, the conversion of compound 12, or a salt thereof,into compound 11, or a salt thereof, is performed in the presence of acyanide source. In some embodiments, the cyanide source is sodiumcyanide (NaCN).

In some embodiments, compound 12:

or a salt thereof, is prepared by converting compound 13:

or a salt thereof, into compound 12, or a salt thereof.

In some embodiments, the conversion of compound 13, or a salt thereof,into compound 12, or a salt thereof, is performed in the presence of aphosphine, a source of bromine, and at least one sixteenth base. In someembodiments, the phosphine is triphenylphosphine (PPh₃). In someembodiments, the source of bromine is molecular bromine (Br₂). In someembodiments, the at least one sixteenth base is pyridine.

In some embodiments, compound 13:

or a salt thereof, is prepared by converting compound 14:

or a salt thereof, into compound 13, or a salt thereof.

In some embodiments, the conversion of compound 14, or a salt thereof,into compound 13, or a salt thereof, is performed in the presence of areducing agent. In some embodiments, the reducing agent is selected fromlithium aluminum hydride (LiAlH₄), boron trifluoride/sodium borohydride(BF₃/NaBH₄), borane (BH₃) and borane complexes such as boranedimethylsulfide (BH₃SMe₂) and borane-tetrahydrofuran (BH₃-THF), Vitride(sodium bis(2-imethoxyethoxy)aluminium hydride), zinc borohydride(Zn(BH₄)₂), and diisobutylaluminum hydride (DIBAL-H).

In some embodiments, compound 14:

or a salt thereof, is prepared by converting compound 15:

or a salt thereof, into compound 14, or a salt thereof.

In some embodiments, the conversion of compound 15, or a salt thereof,into compound 14, or a salt thereof, is performed in the presence ofsodium hydroxide (NaOH) in MeOH.

In some embodiments, compound 13:

or a salt thereof, is prepared by converting compound 15:

or a salt thereof, into compound 13, or a salt thereof.

In some embodiments, compound 15:

or a salt thereof, is prepared by converting compound 16:

or a salt thereof, into compound 15, or a salt thereof.

In some embodiments, the conversion of compound 16, or a salt thereof,into compound 15, or a salt thereof, is performed in the presence ofethyl 2-diazoacetate and copper triflate (Cu(OTf)₂). In someembodiments, the metal catalyst is rhodium (II) acetate dimer(Rh₂(OAc)₄). In some embodiments, the conversion of compound 16, or asalt thereof, into compound 15, or a salt thereof, is performed in thepresence of an enzyme.

In some embodiments, compound 16:

or a salt thereof, is prepared by converting compound 17:

or a salt thereof, into compound 16, or a salt thereof.

In some embodiments, the conversion of compound 17, or a salt thereof,into compound 16, or a salt thereof, is performed in the presence of atleast one seventeenth base. In some embodiments, the at least oneseventeeth base is potassium t-butoxide (KOt-Bu).

In some embodiments, compound 17:

or a salt thereof, is prepared by converting compound 18:

or a salt thereof, into compound 17, or a salt thereof.

In some embodiments, the combination of compound 18, or a salt thereof,with compound 17, or a salt thereof, is performed in the presence of aphosphine, a source of bromine, and at least one eighteenth base. Insome embodiments, the phosphine is triphenylphosphine (PPh₃). In someembodiments, the source of bromine is molecular bromine (Br₂). In someembodiments, the at least one eighteenth base is pyridine.

In some embodiments, compound 18:

or a salt thereof, is prepared by converting compound 19:

or a salt thereof, into compound 18, or a salt thereof.

In some embodiments, the conversion of compound 19, or a salt thereof,into compound 18, or a salt thereof, is performed in the presence ofethyl magnesium bromine (EtMgBr) and titanium (IV) isopropoxide(Ti(Oi-Pr)₄).

In some embodiments, compound 6:

or a salt thereof, is prepared by converting compound 20:

or a salt thereof, into compound 6, or a salt thereof.

In some embodiments, the conversion of compound 20, or a salt thereof,into compound 6, or a salt thereof, is performed in the presence ofpotassium hydroxide (KOH) in methanol (MeOH).

In some embodiments, compound 20:

or a salt thereof, is prepared by converting compound 21:

or a salt thereof, into compound 20, or a salt thereof.

In some embodiments, the conversion of compound 21 into compound 20 isperformed in the presence of hydrochloric acid (HCl).

In some embodiments, compound 21:

or a salt thereof, is prepared by combining compound 22:

with compound 23:

or a salt thereof, to produce compound 21, or a salt thereof.

In some embodiments, the combination of compound 22 with compound 23, ora salt thereof, is performed in the presence of at least one nineteethbase.

In some embodiments, compound 23:

or a salt thereof, is prepared by converting compound 24:

or a salt thereof, into compound 23, or a salt thereof.

In some embodiments, the conversion of compound 24, or a salt thereof,into compound 23, or a salt thereof, is performed in the presence ofdihydropyran and p-toluenesulfonic acid (pTsOH).

In some embodiments, compound 24:

or a salt thereof, is prepared by converting compound 25:

into compound 24, or a salt thereof.

In some embodiments, the conversion of compound 25 into compound 24, ora salt thereof, is performed in the presence of hydrazine.

In some embodiments, compound 15:

or a salt thereof, is prepared by converting compound 26:

into compound 15, or a salt thereof.

In some embodiments, the conversion of compound 26 into compound 15, ora salt thereof, is performed in the presence ofcyclopropyl(diphenyl)sulfonium (tetrafluoroborate) and at least onetwentieth base. In some embodiments, the at least one twentieth base iscesium hydroxide hydrate (Cs(OH)₂.xH₂O).

In some embodiments, compound 26:

is prepared by converting compound 27:

into compound 26.

In some embodiments, the conversion of compound 27 into compound 26 isperformed in the presence of ethyl (triphenylphosphoranylidene) acetate.

In some embodiments, compound 10:

or a salt thereof, is prepared by converting compound 14:

or a salt thereof, into compound 10, or a salt thereof.

In some embodiments, the conversion of compound 14, or a salt thereof,into compound 10, or a salt thereof, is performed in the presence ofthionyl chloride, followed by diazomethane.

In some embodiments, compound 10:

or a salt thereof, is prepared by converting compound 28:

or a salt thereof, into compound 10, or a salt thereof.

In some embodiments, the conversion of compound 28, or a salt thereof,into compound 10, or a salt thereof, is performed in the presence ofhydrazine.

In some embodiments, compound 28:

or a salt thereof, is prepared by converting compound 16:

into compound 28, or a salt thereof.

In some embodiments, the conversion of compound 16 into compound 28, ora salt thereof, is performed in the presence of rhodium(II) octanoatedimer and compound 28, or a salt thereof.

In some embodiments, the compound of Formula (XI):

or a salt thereof, is compound 30:

or a salt thereof.

In some embodiments, compound 30, or a salt thereof, is prepared byconverting compound 31:

or a salt thereof, into compound 30, or a salt thereof.

In some embodiments, the conversion of compound 31, or a salt thereof,into compound 30, or a salt thereof, comprises:

1) reacting compound 31, or a salt thereof, in the presence oftrifluoroacetic acid; and

2) combining the product of step 1) with phthalic anhydride to producecompound 30, or a salt thereof.

In some embodiments, compound 31:

or a salt thereof, is prepared by converting compound 32:

or a salt thereof, into compound 31, or a salt thereof.

In some embodiments, the conversion of compound 32, or a salt thereof,into compound 31, or a salt thereof, is performed in the presence of ahydrogen source, a metal catalyst, and at least one twenty-first base.In some embodiments, the source of hydrogen is hydrogen gas. In someembodiments, the metal catalyst is Raney Ni. In some embodiments, the atleast one twenty-first base is potassium carbonate (K₂CO₃).

In some embodiments, compound 32:

or a salt thereof, is prepared by converting compound 33:

or a salt thereof, into compound 32, or a salt thereof.

In some embodiments, the conversion of compound 33, or a salt thereof,into compound 32, or a salt thereof, is performed in the presence of asulfonyl chloride and at least one twenty-second base. In someembodiments, the sulfonyl chloride is p-toluenesulfonyl chloride. Insome embodiments, the at least one twenty-second base is triethylamine(Et₃N) and trimethylamine hydrochloride.

In some embodiments, compound 33:

or a salt thereof, is prepared by converting compound 34:

or a salt thereof, into compound 33, or a salt thereof.

In some embodiments, the conversion of compound 34, or a salt thereof,into compound 33, or a salt thereof, comprises:

1) reacting compound 34, or a salt thereof, with a carboxylic acidactivating agent; and

2) reacting the product of step 1) with a reducing agent.

In some embodiments, the activating agent is carbonyl diimidazole. Insome embodiments, the reducing agent is sodium borohydride (NaBH₄).

In some embodiments, compound 34:

or a salt thereof, is prepared by converting compound (f)-34:

or a salt thereof, into compound 34, or a salt thereof.

In some embodiments, the conversion of compound (f)-34, or a saltthereof, into compound 34, or a salt thereof, comprises:

1) reacting compound (f)-34 with a chiral amine; and

2) reacting the product of step 1) with an acid.

In some embodiments, the chiral amine is (R)-(−)-a-methylbenzylamine. Insome embodiments, the acid is hydrochloric acid (HCl).

In some embodiments, compound (f)-34:

or a salt thereof, is prepared by converting compound 35:

or a salt thereof, into compound (f)-34, or a salt thereof.

In some embodiments, the conversion of compound 35, or a salt thereof,into compound (f)-34, or a salt thereof, is performed in the presence ofa hydroxide base. In some embodiments, the hydroxide base is sodiumhydroxide (NaOH).

In some embodiments, compound 35:

or a salt thereof, is prepared by converting compound 36:

or a salt thereof, into compound 35, or a salt thereof.

In some embodiments, compound 36:

or a salt thereof, is prepared by converting compound 37:

or a salt thereof, into compound 36, or a salt thereof.

In some embodiments, compound 37:

or a salt thereof, is prepared by converting compound 38:

or a salt thereof, into compound 37, or a salt thereof.

In some embodiments, the conversion of compound 38, or a salt thereof,into compound 37, or a salt thereof, comprises:

1) reacting compound 38, or a salt thereof, with3-tert-butoxycarbonylamino-propionic acid and a coupling reagent; and

2) reacting the product of step 1) with a reducing agent.

In some embodiments, the coupling agent is DCC. In some embodiments,step 1) further comprises DMAP. In some embodiments, the reducing agentis sodium borohydride. In some embodiments, step 2) further comprisesadding acetic acid.

In some embodiments, compound 3:

or a salt thereof, is prepared by converting compound 39:

or a salt thereof, into compound 3, or a salt thereof.

In some embodiments, the conversion of compound 39, or a salt thereof,into compound 3, or a salt thereof, is performed in the presence of areducing reaction conditions. In some embodiments, the reducing reactionconditions are a source of hydrogen and a metal catalyst. In someembodiments, the source of hydrogen is hydrogen gas. In someembodiments, the metal catalyst is Raney Ni.

In some embodiments, compound 39:

or a salt thereof, is prepared by converting compound (±)-39:

or a salt thereof, into compound 39, or a salt thereof.

In some embodiments, the conversion of compound (±)-39, or a saltthereof, into compound 39, or a salt thereof, is performed in thepresence of an enzyme. In some embodiments, the enzyme is palataseenzyme.

In some embodiments, compound (±)-39:

or a salt thereof, is prepared by converting compound (±)-4:

or a salt thereof, into compound (±)-39, or a salt thereof.

In some embodiments, compounds useful for the synthesis of Compound Iare chosen from:

and salts thereof,wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro;

X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I;

X^(d) is selected from F, Cl, Br, and I;

R³ is a monovalent nitrogen protecting group;

R⁴ is —SO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and

wherein the compound is not:

or a salt thereof.

In some embodiments, R is independently selected from methyl andp-tolyl.

In some embodiments, each monovalent nitrogen protecting group isindependently selected from t-butyloxycarbonyl (Boc), benzyl (Bn),tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA),trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, R¹ and R²,together with the atoms to which they are attached, form a nitrogenprotecting group selected from benzylidene,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide,N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl amine,N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide,N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

List of Exemplary Embodiments

1. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (I):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof, wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(c) is selected from F, Cl, Br, and I.

2. The method of embodiment 1, wherein X^(a) is Br and X^(c) is F.3. The method of embodiment 1, wherein the conversion of the compound ofFormula (I), or a salt thereof, into Compound I, or a pharmaceuticallyacceptable salt thereof, comprises the steps of:

1) combining the compound of Formula (I), or a salt thereof, with atleast one first base to produce a compound of Formula (II):

or a salt thereof; and

2) combining the compound of Formula (II), or a salt thereof, withcompound 1:

or a salt thereof,and at least one second base to produce Compound I, or apharmaceutically acceptable salt thereof,wherein in the compound of Formula (II), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.        4. The method of embodiment 3, wherein in the compound of        Formula (II), or a salt thereof, X^(a) is Br.        5. The method of embodiment 3 or 4, wherein the at least one        first base is selected from carbonate bases, hydroxide bases,        alkoxide bases, acetate bases, amine bases, phosphate bases, and        sulfate bases.        6. The method of any one of embodiments 3 to 5, wherein the at        least one first base is selected from sodium carbonate (Na₂CO₃),        potassium carbonate (K₂CO₃), 2,2,6,6-tetramethylpiperidine,        1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),        7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),        t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO₃), and        potassium phosphate tribasic (K₃PO₄).        7. The method of any one of embodiments 3 to 6, wherein the at        least one second base is potassium carbonate (K₂CO₃).        8. The method of any one of embodiments 3 to 7, wherein the        combination of the compound of Formula (II), or a salt thereof,        with compound 1, or a salt thereof, further comprises at least        one metal catalyst.        9. The method of embodiment 8, wherein the at least one metal        catalyst is selected from palladium catalysts and copper        catalysts.        10. The method of embodiment 9, wherein the palladium catalyst        is selected from        [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate (tBuXPhos Pd G3),        [1,1′-bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II),        tris(dibenzylideneacetone)dipalladium(0)        (Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,        Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,        Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,        5′-triphenyl-1′H-[1,4′]bipyrazole,        Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,        Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,        Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl        (Pd₂dba₃/BrettPhos),        Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,        Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,        dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),        Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,        dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II),        (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate,        dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)        (Pd(BINAP)Cl₂), Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether        (Pd₂dba₃/DPEPhos),        Pd₂dba₃/1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,        Pd₂dba₃/2-(di-tertbutylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,        Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,        Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,        2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃        (tert-Butyl XPhos/Pd₂dba₃),        [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)        chloride (tBuXPhos-Pd-GT),        allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)        palladium(II) triflate,        [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate (t-BuBrettPhos-Pd-G3),        2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃        (t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonate        allyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]        palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)        [2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate/Pd₂dba₃ (SPhos/Pd₂dba₃),        [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II)        (Pd(dppf)Cl₂,        [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)        (Pd(dtbpf)Cl₂),        dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)        (PEPSIIpent),        di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃        (cBRIDP/Pd₂dba₃), and        1-(dicyclohexylphosphino)-2,2-Diphenyl-1-methylcyclopropane/Pd₂dba₃        (Cy-cBRIDP/Pd₂dba₃).        11. The method of embodiment 9, wherein the copper catalyst is        selected from copper(II) fluoride, copper(I) bromide (CuBr),        copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and        copper(I) trifluoromethanesulfonate toluene complex, optionally        substituted with a ligand such as N,N′-dimethylethylenediamine,        N,N′-dimethylcyclohexane-1,2-diamine), 1,10-phenanthroline,        8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,        cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic        acid, 2,2′-bipyridine, 2-acetylcyclohexanone,        1,3-di-tert-butyl-1,3-propanedione, rac-BINOL,        dipivaloylmethane, 2-isobutyrylcyclohexanone,        2-amino-4,6-pyrimidinediol,        (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol,        salicylaldoxime, glycolic acid, L-proline, 2,2′-dipyridyl, and        N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine,        N,N-diisopropyl-1,3-propanediamine,        trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,3-propanediamine,        N,N′-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine,        1,4-diaminocyclohexane, N,N′-dimethylethane-1,2-diamine,        diethylenetriamine, and        trans-N,N-dimethylcyclohexane-1,2-diamine.        12. The method of any one of embodiments 8 to 11, wherein the at        least one metal catalyst is        [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]        palladium(II) methanesulfonate (tBuXPhos Pd G3),        bis(dibenzylideneacetone)palladium(0) (Pd₂dba₃), copper iodide        (CuI), or a combination thereof.        13. The method of any one of embodiments 8 to 12, wherein the        combination of the compound of Formula (II), or a salt thereof,        with compound 1, or a salt thereof, further comprises excess        2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl        (tBuXPhos) relative to        [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]        palladium(II) methanesulfonate (tBuXPhos Pd G3).        14. The method of embodiment 1, wherein the conversion of the        compound of Formula (I), or a salt thereof, into Compound I, or        a pharmaceutically acceptable salt thereof, comprises combining        the compound of Formula (I), or a salt thereof, with compound 1:

or a salt thereof, and at least one third base to produce Compound I, ora pharmaceutically acceptable salt thereof,wherein in the compound of Formula (I), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(c) is selected from F, Cl, Br, and I.

15. The method of embodiment 14, wherein in the compound of Formula (I),or a salt thereof, X^(a) is Br and X^(c) is F.16. The method of embodiment 14 or 15, wherein the at least one thirdbase is selected from carbonate bases, hydroxide bases, alkoxide bases,acetate bases, amine bases, phosphate bases, and sulfate bases.17. The method of any one of embodiments 14 to 16, wherein the at leastone third base is selected from sodium carbonate (Na₂CO₃), potassiumcarbonate (K₂CO₃), 2,2,6,6-tetramethylpiperidine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO₃), and potassiumphosphate tribasic (K₃PO₄).18. The method of any one of embodiments 14 to 17, wherein the at leastone third base is potassium carbonate (K₂CO₃).19. The method of any one of embodiments 14 to 18, wherein thecombination of the compound of Formula (I), or a salt thereof, withcompound 1, or a salt thereof, further comprises at least one metalcatalyst.20. The method of embodiment 19, wherein the at least one metal catalystis selected from palladium catalysts and copper catalysts.21. The method of embodiment 20, wherein the palladium catalyst isselected from[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3),[1,1′-bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,5′-triphenyl-1′H-[1,4′]bipyrazole,Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(Pd₂dba₃/BrettPhos),Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)(Pd(BINAP)Cl₂), Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether(Pd₂dba₃/DPEPhos),Pd₂dba₃/1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,Pd₂dba₃/2-(di-tertbutylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃(tert-Butyl XPhos/Pd₂dba₃),[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)chloride (tBuXPhos-Pd-GT),allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (t-BuBrettPhos-Pd-G3),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃(t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonateallyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate/Pd₂dba₃(SPhos/Pd₂dba₃),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)(Pd(dtbpf)Cl₂),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPSIIpent),di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃(cBRIDP/Pd₂dba₃), and1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane/Pd₂dba₃(Cy-cBRIDP/Pd₂dba₃).22. The method of embodiment 20, wherein the copper catalyst is selectedfrom copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide(CuI), copper(I) thiophene-2-carboxylate, and copper(I)trifluoromethanesulfonate toluene complex, optionally substituted with aligand such as N,N′-dimethylethylenediamine,N,N′-dimethylcyclohexane-1,2-diamine), 1,10-phenanthroline,8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid,2,2′-bipyridine, 2-acetylcyclohexanone,1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane,2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol,(1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime,glycolic acid, L-proline, 2,2′-dipyridyl, andN-cyclohexyl-2,6-bis(1-methylethyl)benzenamine,N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane,N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine,3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane,N,N′-dimethylethane-1,2-diamine, diethylenetriamine, andtrans-N,N-dimethylcyclohexane-1,2-diamine.23. The method of any one of embodiments 19 to 22, wherein the at leastone metal catalyst is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3),bis(dibenzylideneacetone)palladium(0) (Pd₂dba₃), copper iodide (CuI), ora combination thereof.24. The method of any one of embodiments 19 to 23, wherein thecombination of the compound of Formula (I), or a salt thereof, withcompound 1, or a salt thereof, further comprises excess2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos)relative to[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3).25. The method of any one of embodiments 1 and 3 to 24, wherein thecompound of Formula (I):

or a salt thereof, is prepared by converting a compound of Formula(III):

or a salt thereof, into the compound of Formula (I), or a salt thereof,wherein in the compound of Formula (III), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro;

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

26. The method of embodiment 25, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).27. The method of embodiment 25, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.28. The method of embodiment 25 or 27, wherein in the compound ofFormula (III), or a salt thereof, X^(a) is Br, X^(c) is F, and R¹ andR², together with the atoms to which they are attached, formN-phthalimide.29. The method of embodiment 28, wherein the conversion of the compoundof Formula (III), or a salt thereof, into the compound of Formula (I),or a salt thereof, comprises the steps of:

1) combining the compound of Formula (III), or a salt thereof, in thepresence of water and a base selected from lithium hydroxide (LiOH),hydrazine, ethanolamine, and N-methylamine; and

2) optionally combining the product of step 1) with an acid selectedfrom oxalic acid, hydrochloric acid (HCl), phosphoric acid (H₃PO₄), andcitric acid; then treating the reaction mixture with water and a baseselected from potassium carbonate (K₂CO₃) and cesium carbonate (Cs₂CO₃)to produce the compound of Formula (I), or a salt thereof.

30. The method of any one of embodiments 25 to 27 and 29, wherein thecompound of Formula (III):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (III), or a saltthereof,wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro

X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

31. The method of embodiment 30, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).32. The method of embodiment 30, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.33. The method of embodiment 30 or 32, wherein in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, and R¹ and R², togetherwith the atoms to which they are attached, form N-phthalimide.34. The method of embodiment 30 or 31, wherein in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, R¹ is hydrogen, and R² isbenzyloxycarbonyl (Cbz).35. The method of any one of embodiments 30 to 34, wherein in thecompound of Formula (V), or a salt thereof, X^(b) is —OC₆F₅ and X^(c) isF.36. The method of any one of embodiments 30 to 35, wherein thecombination of the compound of Formula (IV), or a salt thereof, with thecompound of Formula (V), or a salt thereof, is performed in the presenceof at least one fourth base.37. The method of embodiment 36, wherein the at least one fourth base isan alkoxy base.38. The method of embodiment 37, wherein the alkoxy base is selectedfrom lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassiumt-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu).39. The method of any one of embodiments 30 to 32 and 35 to 38, whereinthe compound of Formula (IV):

or a salt thereof, is prepared by converting a compound of Formula (VI):

or a salt thereof, into the compound of Formula (IV), or a salt thereof,wherein in the compound of Formula (VI), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.        40. The method of embodiment 39, wherein in the compound of        Formula (VI), or a salt thereof, X^(a) is Br.        41. The method of embodiment 39 or 40, wherein the conversion of        the compound of Formula (VI), or a salt thereof, into the        compound of Formula (IV), or a salt thereof, comprises the steps        of:

1) converting the hydroxy group of the compound of formula (VI), or asalt thereof, into a sulfonate ester (—OSO₂R) or Cl; and

2) combining the sulfonate ester or Cl of step 1) with an amine and atleast one fifth base to produce the compound of Formula (IV), or a saltthereof.

42. The method of embodiment 41, wherein the R group of the sulfonateester (—OSO₂R) is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryloptionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, ornitro.43. The method of embodiment 41, wherein the conversion of the hydroxygroup into a sulfonate ester in step 1) is performed in the presence ofmethanesulfonyl chloride (MsCl) and triethylamine (Et₃N).44. The method of embodiment 41 or 42, wherein the amine in step 2) isN-phthalimide and the at least one fifth base is potassium carbonate(K₂CO₃).45. The method of any one of embodiments 39 and 41 to 44, wherein thecompound of Formula (VI):

or a salt thereof, is prepared by combining compound 2:

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (VI), or a saltthereof,wherein in the compound of Formula (VII), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(d) is selected from F, Cl, Br, and I.

46. The method of embodiment 45, wherein in the compound of Formula(VII), or a salt thereof, X^(a) is Br and X^(d) is F.47. The method of any one of embodiments 45 or 46, wherein thecombination of compound 2, or a salt thereof, with the compound ofFormula (VII), or a salt thereof, is performed in the presence of atleast one sixth base.48. The method of embodiment 47, wherein the at least one sixth base isselected from potassium t-butoxide (KOt-Bu), lithium hydroxide (LiOH),potassium phosphate tribasic (K₃PO₄), potassium phosphate dibasic(K₂HPO₄), cesium carbonate (Cs₂CO₃), 2,2,6,6-tetramethylpiperidine,7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),triethylamine (Et₃N), tributylamine (Bu₃N), sodium bicarbonate (NaHCO₃),potassium bicarbonate (KHCO₃), sodium carbonate (Na₂CO₃) and potassiumcarbonate (K₂CO₃).49. The method of any one of embodiments 45 to 48, wherein thecombination of compound 2, or a salt thereof, with the compound ofFormula (VII), or a salt thereof, is performed in the presence ofpotassium carbonate (K₂CO₃), water, and 2-methyltetrahydrofuran(2-MeTHF).50. The method of any one of embodiments 45 to 49, wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.51. The method of embodiment 50, wherein the conversion of compound 3,or a salt thereof, into compound 2, or a salt thereof, is performed inthe presence of a reducing agent or reducing reaction conditions.52. The method of embodiment 51, wherein the reducing agent is lithiumaluminum hydride (LiAH₄).53. The method of any one of embodiments 50 to 52, wherein compound 3:

or a salt thereof, is prepared by converting compound 4:

or a salt thereof, into compound 3, or a salt thereof.54. The method of embodiment 53, wherein the conversion of compound 4,or a salt thereof, into compound 3, or a salt thereof, is performed inthe presence of reducing reaction conditions.55. The method of embodiment 54, wherein the reducing reactionconditions comprise hydrogen gas (H₂) and at least one metal catalystselected from Raney Nickel (Ra—Ni), palladium on carbon (Pd/C),palladium on alumina (Pd/Al₂O₃), palladium(II) chloride (PdCl₂),platinum oxide (PtO₂), palladium/platinum on carbon (Pd/Pt/C), platinumon carbon (Pt/C), and nickel(II) chloride/sodium borohydride(NiCl₂/NaBH₄).56. The method of any one of embodiments 53 to 55, wherein compound 4:

or a salt thereof, is prepared by chiral resolution of compound (±)-4:

or a salt thereof.57. The method of embodiment 56, wherein the chiral resolution ofcompound (±)-4, or a salt thereof, is performed using a method selectedfrom chiral column chromatography, chiral Simulated Moving Bed (SMB)chromatography, bioresolution, enzymatic resolution, liquidchromatography, salt resolution, and asymmetric hydrogenation.58. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (VIII):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof,wherein in the compound of Formula (VIII), or a salt thereof, X^(c) isselected from F, Cl, Br, and I.59. The method of embodiment 58, wherein the conversion of the compoundof Formula (VIII), or a salt thereof, into Compound I, or apharmaceutically salt thereof, is performed in the presence of at leastone seventh base.60. The method of embodiment 59, wherein the at least one seventh baseis selected from potassium carbonate (K₂CO₃),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine(DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,1,3,3-tetramethylguanidine, potassium hydroxide (KOH), potassiumhydroxide/Triton B (KOH/Triton B), potassiumhydroxide//tetra-n-butylammonium iodide (KOH/nBu₄NH₄I), potassiumhydroxide/tetra-n-octylammonium bromide (KOH/n-Oct₄NH₄Br), lithiumhydroxide (LiOH), and lithium carbonate (Li₂CO₃).61. The method of embodiment 59 or 60, wherein the at least one seventhbase is potassium carbonate (K₂CO₃).62. The method of embodiment 61, wherein the conversion of the compoundof Formula (VIII), or a salt thereof, into Compound I, or apharmaceutically acceptable salt thereof, further comprises magnesiumchloride (MgCl₂).63. The method of any one of embodiments 58 to 62, wherein the compoundof Formula (VIII):

or a salt thereof, is prepared by converting a compound of Formula (IX):

or a salt thereof, into the compound of Formula (VIII), or a saltthereof,wherein in the compound of Formula (IX), or a salt thereof:

X^(c) is selected from F, Cl, Br, and I; and

wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

64. The method of embodiment 63, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).65. The method of embodiment 63, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.66. The method of embodiment 63 or 64, wherein in the compound ofFormula (IX), or a salt thereof, X^(c) is F, R¹ is hydrogen, and R² isbenzyloxycarbonyl (Cbz).67. The method of any one of embodiments 63 to 66, wherein theconversion of the compound of Formula (IX), or a salt thereof, into thecompound of Formula (VIII), or a salt thereof, is performed in thepresence of reducing reaction conditions.68. The method of embodiment 67, wherein the reducing reactionconditions are selected from hydrogen gas (H₂) and palladium on carbon(Pd/C), formic acid/triethylamine/palladium on carbon(HCO₂H/Et₃N/(Pd/C)), ammonium formate/potassium carbonate and palladiumon carbon (NH₄HCO₂/K₂CO₃ and Pd/C), potassium phosphate dibasic andpalladium on carbon (K₂HPO₄ and Pd/C), potassium phosphate and palladiumon carbon (K₃PO₄ and Pd/C), hydrazine and palladium on carbon(NH₂NH₂/(Pd/C)), and 1,4-cyclohexadiene and palladium on carbon.69. The method of any one of embodiments 63 to 65, 67, and 68, whereinthe compound of Formula (IX):

or a salt thereof, is prepared by combining a compound of Formula (X):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (IX), or a saltthereof,wherein in the compound of Formula (X), or a salt thereof:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and

wherein in the compound of Formula (V), or a salt thereof:

X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I.

70. The method of embodiment 69, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).71. The method of embodiment 69, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.72. The method of any one of embodiments 69 to 71, wherein in thecompound of Formula (X), or a salt thereof, R¹ is hydrogen and R² isCbz, or R¹ and R², together with the atoms to which they are attached,form N-phthalimide.73. The method of any one of embodiments 69 to 72, wherein in thecompound of Formula (V), or a salt thereof, X^(b) is —OC₆F₅ and X^(c) isF.74. The method of any one of embodiments 69 to 73, wherein thecombination of the compound of Formula (X), or a salt thereof, with thecompound of Formula (V), or a salt thereof, is performed in the presenceof at least one eighth base.75. The method of embodiment 74, wherein the at least one eighth base isan alkoxy base.76. The method of embodiment 75, wherein the alkoxy base is selectedfrom lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassiumt-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu).77. The method of any one of embodiments 69 to 76, wherein the compoundof Formula (X):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with compound 1:

or a salt thereof, to produce the compound of Formula (X), or a saltthereof,wherein in the compound of Formula (IV), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group.

78. The method of embodiment 77, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).79. The method of embodiment 77, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.80. The method of embodiment 77 or 79, wherein in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, and R¹ and R², togetherwith the atoms to which they are attached, form N-phthalimide.81. The method of embodiment 77 or 78, wherein in the compound ofFormula (IV), or a salt thereof, X^(a) is Br, R¹ is hydrogen, and R² isbenzyloxycarbonyl (Cbz).82. The method of any one of embodiments 77 to 81, wherein thecombination of the compound of Formula (IV), or a salt thereof, withcompound 1, or a salt thereof, is performed in the presence of at leastone ninth base.83. The method of embodiment 82, wherein the at least one ninth base isselected from carbonate bases, hydroxide bases, alkoxide bases, acetatebases, amine bases, phosphate bases, and sulfate bases.84. The method of embodiment 82 or 83, wherein the at least one ninthbase is selected from sodium carbonate (Na₂CO₃), potassium carbonate(K₂CO₃), cesium carbonate (Cs₂CO₃), lithium carbonate (Li₂CO₃), sodiumhydroxide (NaOH) optionally in THF, MeTHF, or IPA, potassium hydroxide(KOH), sodium tert-butoxide (NaOt-Bu) optionally in THF, MeTHF, or IPA,potassium tert-butoxide (NaOt-Bu), pyridine,2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)optionally in IPA, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),t-Bu-tetramethylguanidine, N,N-diisopropylethylamine (DIPEA), potassiumbis(trimethylsilyl)amide (KHMDS), pyridine, sodium bicarbonate (NaHCO₃),potassium bicarbonate (KHCO₃), sodium phosphate tribasic (Na₃PO₄), andpotassium phosphate tribasic (K₃PO₄).85. The method of any one of embodiments 82 to 84, wherein the at leastone ninth base is potassium carbonate (K₂CO₃).86. The method of any one of embodiments 77 to 85, wherein thecombination of the compound of Formula (IV), or a salt thereof, withcompound 1, or a salt thereof, further comprises at least one metalcatalyst.87. The method of embodiment 86, wherein the at least one metal catalystis selected from palladium catalysts and copper catalysts.88a. The method of embodiment 87, wherein the palladium catalyst isselected from[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuXPhos Pd G3),[1,1′-bis(di-tertbutylphosphino)ferrocene]dichloro palladium(II),tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃)/2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd₂dba₃/N-phenyl-2-(di-tert-butylphosphino)pyrrole,Pd₂dba₃/2-di-tert-butylphosphino-2′-methylbiphenyl,Pd₂dba₃/5-(di-tert-butylphosphino)-1′, 3′,5′-triphenyl-1′H-[1,4′]bipyrazole,Pd₂dba₃/2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole,Pd₂dba₃/2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,Pd₂dba₃/2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(Pd₂dba₃/BrettPhos),Pd₂dba₃/di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine,Pd₂dba₃/1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),Pd₂dba₃/1,1′-bis(diphenylphosphino)ferrocene,dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (XPhos Pd G3),dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II)(Pd(BINAP)Cl₂, Pd₂dba₃/bis[(2-diphenylphosphino)phenyl] ether(Pd₂dba₃/DPEPhos),Pd₂dba₃/1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene,Pd₂dba₃/2-(di-tertbutylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,Pd₂dba₃/2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,Pd₂dba₃/1,1′-bis(di-tert-butylphosphino)ferrocene,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl/Pd₂dba₃(tert-Butyl XPhos/Pd₂dba₃),[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)chloride (tBuXPhos-Pd-G1),allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (t-BuBrettPhos-Pd-G3),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl/Pd₂dba₃(t-BuBrettPhos/Pd₂dba₃), trifluoromethanesulfonateallyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate/Pd₂dba₃(SPhos/Pd₂dba₃), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl₂,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)(Pd(dtbpf)Cl₂),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPSIIpent),di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine/Pd₂dba₃(cBRIDP/Pd₂dba₃), and1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane/Pd₂dba₃(Cy-cBRIDP/Pd₂dba₃).88b. The method of embodiment 87, wherein the active catalyst, palladium(0) 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) is generated using palladium (II) tBuXPhos precatalyst(G1-G3) or a combination of a palladium (0) source, for examplePd₂(dba)₃ or Pd(PPh₃)₄, anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos) and finally by using palladium (II) source, such asPd(OAc)₂ or Pd(Cl)₂ in the presence of a reducing agent anddi-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos,tert-Butyl XPhos).89. The method of embodiment 87, wherein the copper catalyst is selectedfrom copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide(CuI), copper(I) thiophene-2-carboxylate, and copper(I)trifluoromethanesulfonate toluene complex, optionally substituted with aligand such as N,N′-dimethylethylenediamine,N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline,8-hydroxyquinoline, trans-cyclohexane-1,2-diamine,cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid,2,2′-bipyridine, 2-acetylcyclohexanone,1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane,2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol,(1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime,glycolic acid, L-proline, 2,2′-dipyridyl,N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine,N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane,N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine,3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane,N,N′-dimethylethane-1,2-diamine, diethylenetriamine, andtrans-N,N-dimethylcyclohexane-1,2-diamine.90. The method of any one of embodiments 86 to 89, wherein the at leastone metal catalyst is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3),bis(dibenzylideneacetone)palladium(0) (Pd₂dba₃), copper iodide (CuI), ora combination thereof.91. The method of any one of embodiments 77 to 88, wherein thecombination of the compound of Formula (IV), or a salt thereof, withcompound 1, or a salt thereof, further comprises copper iodide (CuI).92. The method of embodiment 91, wherein the combination of the compoundof Formula (IV), or a salt thereof, with compound 1, or a salt thereof,further comprises dicyclohexylamine (DMCHDA).93. The method of any one of embodiments 77 to 79 and 82 to 92, whereinthe compound of Formula (IV):

or a salt thereof, is prepared by combining a compound of Formula (XI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (IV), or a saltthereof,wherein in the compound of Formula (XI), or a salt thereof:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and

wherein in the compound of Formula (VII), or a salt thereof:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and

X^(d) is selected from F, Cl, Br, and I.

94. The method of embodiment 93, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).95. The method of embodiment 93, wherein R¹ and R², together with theatoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.96. The method of embodiment 93 or 94, wherein in the compound ofFormula (XI), or a salt thereof, R¹ is hydrogen and R² isbenzyloxycarbonyl (Cbz).97. The method of embodiment 93 or 95, wherein in the compound ofFormula (XI), or a salt thereof, R¹ and R², together with the atoms towhich they are attached, form N-phthalimide.98. The method of any one of embodiments 93 to 97, wherein in thecompound of Formula (VII), or a salt thereof, X^(a) is Br and X^(d) isF.99. The method of any one of embodiments 93 to 98, wherein thecombination of the compound of Formula (XI), or a salt thereof, with thecompound of Formula (VII), or a salt thereof, is performed in thepresence of at least one tenth base.100. The method of embodiment 99, wherein the at least one tenth base isa carbonate base.101. The method of embodiment 99 or 100, wherein the at least one tenthbase is potassium carbonate (K₂CO₃).102. The method of embodiment 101, wherein the combination of thecompound of Formula (XI), or a salt thereof, with the compound ofFormula (VII), or a salt thereof, further comprises zinc chloride(ZnCl₂).103. The method of any one of embodiments 93 to 102, wherein thecompound of Formula (XI):

or a salt thereof, is prepared by converting a compound of Formula(XII):

or a salt thereof, into the compound of Formula (XI), or a salt thereof,wherein in the compound of Formula (XII), or a salt thereof, R³ is amonovalent nitrogen protecting group.104. The method of embodiment 103, wherein each monovalent nitrogenprotecting group is selected from t-butyloxycarbonyl (Boc),benzyloxycarbonyl (Cbz), and N-phthalimide.105. The method of embodiment 103 or 104, wherein in the compound ofFormula (XII), or a salt thereof, R³ is t-butyloxycarbonyl (Boc).106. The method of any one of embodiments 103 to 105, wherein theconversion of the compound of Formula (XII), or a salt thereof, into thecompound of Formula (XI), or a salt thereof, comprises the steps of:

1) converting the primary amine of the compound of Formula (XII), or asalt thereof, into a protected amine —NR¹R²; and

2) deprotecting R³ to produce the compound of Formula (XI), or a saltthereof.

107. The method of embodiment 106, wherein the conversion in step 1) isperformed in the presence of benzyl chloroformate (Cbz-Cl) and potassiumhydroxide (KOH).108. The method of embodiment 106 or 107, wherein R³ in step 2) isdeprotected with hydrochloric acid (HCl), methanesulfonic acid (MsOH),or trifluoroacetic acid.109. The method of any one of embodiments 103 to 108, wherein thecompound of Formula (XII):

or a salt thereof, is prepared by converting the compound of Formula(XV):

or a salt thereof, into the compound of Formula (XII), or a saltthereof,wherein in the compound of Formula (XV), or a salt thereof, R³ is amonovalent nitrogen protecting group.110. The method of embodiment 109, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).111. The method of embodiment 109 or 110, wherein in the compound ofFormula (XV), or a salt thereof, R³ is t-butyloxycarbonyl (Boc).112. The method of any one of embodiments 109 to 111, wherein theconversion of the compound of Formula (XV), or a salt thereof, into thecompound of Formula (XII), or a salt thereof, comprises the steps of:

1) converting the compound of Formula (XV):

or a salt thereof, into the compound of Formula (XIV):

or a salt thereof;

2) converting the compound of Formula (XIV), or a salt thereof, into thecompound of Formula (XIII):

or a salt thereof; and

3) converting the compound of Formula (XIII), or a salt thereof, intothe compound of Formula (XII), or a salt thereof,

wherein in the compounds of Formulae (XIII)-(XV), or a salt thereof, R³is a monovalent nitrogen protecting group; and wherein in the compoundof Formula (XIV), or a salt thereof:

R⁴ is —SO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro.        113. The method of embodiment 112, wherein each monovalent        nitrogen protecting group is independently selected from        t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP),        9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz),        formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and        p-toluenesulfonyl (Ts).        114. The method of embodiment 112 or 113, wherein in the        compounds of Formulae (XIII)-(XV), or a salt thereof, R³ is        t-butyloxycarbonyl (Boc).        115. The method of any one of embodiments 112 to 114, wherein in        the compound of Formula (XIV), or a salt thereof, R⁴ is        4-nitrobenzylsulfonyl chloride (NsCl).        116. The method of any one of embodiments 112 to 115, wherein        the conversion of the compound of Formula (XV), or a salt        thereof, into the compound of Formula (XIV), or a salt thereof,        is performed in the presence of 4-nitrobenzylsulfonyl chloride        (NsCl) and at least one eleventh base.        117. The method of embodiment 116, wherein the at least one        eleventh base is an amine base or carbonate base.        118. The method of any one of embodiments 112 to 117, wherein        the conversion of the compound of Formula (XIV), or a salt        thereof, into the compound of Formula (XIII), or a salt thereof,        is performed in the presence of an azide source.        119. The method of embodiment 118, wherein the azide source is        sodium azide (NaN₃).        120. The method of any one of embodiments 112 to 119, wherein        the conversion of the compound of Formula (XIII), or a salt        thereof, into the compound of Formula (XII), or a salt thereof,        is performed in the presence of reducing reaction conditions.        121. The method of embodiment 120, wherein the reducing reaction        conditions comprise hydrogen gas (H₂) and a metal catalyst        selected from platinum dioxide (PtO₂) and palladium on carbon        (Pd/C).        122. The method of any one of embodiments 112 to 121, wherein        the compound of Formula (XV):

or a salt thereof, is prepared by converting compound 2:

or a salt thereof, into the compound of Formula (XV), or a salt thereof.123. The method of embodiment 122, wherein the conversion of compound 2,or a salt thereof, into the compound of Formula (XV), or a salt thereof,is performed in the presence of di-tert-butyl dicarbonate (Boc₂O).124. The method of embodiment 123, further comprising combining thecompound of Formula (XV), or a salt thereof, with L-glutamic acid.125. The method of embodiment 122 or 124, wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.126. The method of embodiment 125, wherein the conversion of compound 3,or a salt thereof, into compound 2, or a salt thereof, is performed inthe presence of a reducing agent and at least one solvent.127. The method of embodiment 126, wherein the reducing agent is lithiumaluminum hydride (LiAlH₄).128. The method of embodiment 127, wherein the at least one solvent is2-methyltetrahydrofuran (2-MeTHF).129. The method of any one of embodiments 125 to 128, wherein compound3:

or a salt thereof, is prepared by chiral resolution of compound (±)-3:

or a salt thereof.130. The method of embodiment 129, wherein the chiral resolution ofcompound (±)-3 is performed using a method selected from chiral columnchromatography, chiral Simulated Moving Bed (SMB) chromatography,bioresolution, enzymatic resolution, liquid chromatography, saltresolution, and asymmetric hydrogenation.131. The method of embodiment 129 or 130, wherein compound (±)-3:

or a salt thereof, is prepared by converting compound (±)-4:

or a salt thereof, into compound (±)-3, or a salt thereof.132. The method of embodiment 131, wherein the conversion of compound(±)-4, or a salt thereof, into compound (±)-3, or a salt thereof, isperformed in the presence of reducing reaction conditions.133. The method of embodiment 132, wherein the reducing reactionconditions comprise hydrogen gas (H₂) and Raney Nickel.134. The method of any one of embodiments 131 to 133, wherein compound(±)-4:

or a salt thereof, is prepared by combining compound 5:

or a salt thereof, with 2-nitropropane to produce compound (±)-4, or asalt thereof.135. The method of embodiment 134, wherein the combination of compound5, or a salt thereof, with 2-nitropropane is performed in the presenceof 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).136. The method of embodiment 134 or 135, wherein compound 5:

or a salt thereof, is prepared by converting δ-valerolactone intocompound 5, or a salt thereof.137. The method of embodiment 136, wherein the conversion ofδ-valerolactone into compound 5, or a salt thereof, comprises the stepsof:

1) combining δ-valerolactone with an alkyl formate and at least onetwelfth base; and

2) combining the product of step 1) with paraformaldehyde.

138. The method of embodiment 137, wherein the method further comprisescontacting the product of step 2) with SiO₂ to produce compound 5, or asalt thereof.139. The method of embodiment 137 or 138, wherein the alkyl formate isethyl formate and the at least one twelfth base is sodium hydride (NaH).140. The method of any one of embodiments 3 to 24 and 77 to 92, whereincompound 1:

or a salt thereof, is prepared by converting compound 6:

or a salt thereof, into compound 1, or a salt thereof.141. The method of embodiment 140, wherein the conversion of compound 6,or a salt thereof, into compound 1, or a salt thereof, is performed inthe presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).142. The method of embodiment 140 or 141, wherein compound 6:

or a salt thereof, is prepared by converting compound 7:

or a salt thereof, into compound 6, or a salt thereof.143. The method of embodiment 142, wherein the conversion of compound 7,or a salt thereof, into compound 6, or a salt thereof, is performed inthe presence of at least one thirteenth base and at least one solvent.144. The method of embodiment 143, wherein the at least one thirteenthbase is potassium hydroxide (KOH).145. The method of embodiment 143 or 144, wherein the at least onesolvent is methanol (MeOH).146. The method of any one of embodiments 142 to 145, wherein compound7:

or a salt thereof, is prepared by combining compound 8:

or a salt thereof, with compound 9:

or a salt thereof, to produce compound 7, or a salt thereof.147. The method of embodiment 146, wherein the combination of compound8, or a salt thereof, with compound 9, or a salt thereof, is performedin the presence of a phosphine and an azodicarboxylate.148. The method of embodiment 147, wherein the phosphine istriphenylphosphine (PPh₃).149. The method of embodiment 147 or 148, wherein the azodicarboxylateis diisopropyl azocarboxylate (DIAD).150. The method of any one of embodiments 146 to 149, wherein thecombination of compound 8, or a salt thereof, with compound 9, or a saltthereof, is performed in the presence of a sulfonyl chloride and atleast one fourteenth base.151. The method of embodiment 150, wherein the sulfonyl chloride ismethanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl).152. The method of embodiment 150 or 151, wherein the at least onefourteenth base is triethylamine (Et₃N).153. The method of any one of embodiments 146 to 152, wherein compound8:

or a salt thereof, is prepared by converting compound 10:

or a salt thereof, into compound 8, or a salt thereof.154. The method of embodiment 153, wherein the conversion of compound10, or a salt thereof, into compound 8, or a salt thereof, is performedin the presence of a reducing agent.155. The method of embodiment 154, wherein the reducing agent isselected from lithium aluminum hydride (LiAlH₄), borontrifluoride/sodium borohydride (BF₃/NaBH₄), borane (BH₃) and boranecomplexes such as borane dimethylsulfide (BH₃SMe₂) andborane-tetrahydrofuran (BH₃-THF), Vitride (sodiumbis(2-methoxyethoxy)aluminium hydride), zinc borohydride (Zn(BH₄)₂), anddiisobutylahminum hydride (DIBAL-H).156. The method of any one of embodiments 153 to 155, wherein compound10:

or a salt thereof, is prepared by converting compound 11:

or a salt thereof, into compound 10, or a salt thereof.157. The method of embodiment 156, wherein the conversion of compound11, or a salt thereof, into compound 10, or a salt thereof, is performedin the presence of at least one fifteenth base and at least one solvent.158. The method of embodiment 157, wherein the at least one fifteenthbase is selected from sodium hydroxide (NaOH), potassium hydroxide(KOH), and barium hydroxide (Ba(OH)₂).159. The method of embodiment 157 or 158, wherein the at least onesolvent is selected from ethanol (EtOH), methanol (MeOH), ethyleneglycol, diethylene glycol, and water.160. The method of any one of embodiments 156 to 159, wherein compound11:

or a salt thereof, is prepared by converting compound 12:

or a salt thereof, into compound 11, or a salt thereof.161. The method of embodiment 160, wherein the conversion of compound12, or a salt thereof, into compound 11, or a salt thereof, is performedin the presence of a cyanide source.162. The method of embodiment 161, wherein the cyanide source is sodiumcyanide (NaCN).163. The method of any one of embodiments 160 or 162, wherein compound12:

or a salt thereof, is prepared by converting compound 13:

or a salt thereof, into compound 12, or a salt thereof.164. The method of embodiment 163, wherein the conversion of compound13, or a salt thereof, into compound 12, or a salt thereof, is performedin the presence of a phosphine, a source of bromine, and at least onesixteenth base.165. The method of embodiment 164, wherein the phosphine istriphenylphosphine (PPh₃).166. The method of embodiment 164 or 165, wherein the source of bromineis molecular bromine (Br₂).167. The method of any one of embodiments 164 to 166, wherein the atleast one sixteenth base is pyridine.168. The method of any one of embodiments 163 to 167, wherein compound13:

or a salt thereof, is prepared by converting compound 14:

or a salt thereof, into compound 13, or a salt thereof.169. The method of embodiment 168, wherein the conversion of compound14, or a salt thereof, into compound 13, or a salt thereof, is performedin the presence of a reducing agent.170. The method of embodiment 169, wherein the reducing agent isselected from lithium aluminum hydride (LiAH₄), boron trifluoride/sodiumborohydride (BF₃/NaBH₄), borane (BH₃) and borane complexes such asborane dimethylsulfide (BH₃SMe₂) and borane-tetrahydrofuran (BH₃-THF),Vitride (sodium bis(2-methoxyethoxy)aluminium hydride), zinc borohydride(Zn(BH₄)₂), and diisobutylailuinum hydride (DIBAL-H).171. The method of any one of embodiments 168 to 170, wherein compound14:

or a salt thereof, is prepared by converting compound 15:

or a salt thereof, into compound 14, or a salt thereof.172. The method of embodiment 171, wherein the conversion of compound15, or a salt thereof, into compound 14, or a salt thereof, is performedin the presence of sodium hydroxide (NaOH) in methanol (MeOH).173. The method of embodiment 171 or 172, wherein compound 15:

or a salt thereof, is prepared by converting compound 16:

or a salt thereof, into compound 15, or a salt thereof.174. The method of embodiment 173, wherein the conversion of compound16, or a salt thereof, into compound 15, or a salt thereof, is performedin the presence of ethyl 2-diazoacetate and a metal catalyst.175. The method of embodiment 174, wherein the metal catalyst isrhodium(II) acetate dimer (Rh₂(OAc)₄) or copper triflate (Cu(OTf)₂).176. The method of any one of embodiments 173 to 175, wherein compound16:

or a salt thereof, is prepared by converting compound 17:

or a salt thereof, into compound 16, or a salt thereof.177. The method of embodiment 176, wherein the conversion of compound17, or a salt thereof, into compound 16, or a salt thereof, is performedin the presence of at least one seventeeth base.178. The method of embodiment 177, wherein the at least one seventeenthbase is potassium t-butoxide (KOt-Bu).179. The method of any one of embodiments 176 to 178, wherein compound17:

or a salt thereof, is prepared by converting compound 18:

or a salt thereof, into compound 17, or a salt thereof.180. The method of embodiment 179, wherein the combination of compound18, or a salt thereof, with compound 17, or a salt thereof, is performedin the presence of a phosphine, a source of bromine, and at least oneeighteenth base.181. The method of embodiment 180, wherein the phosphine istriphenylphosphine (PPh₃).182. The method of embodiment 180 or 181, wherein the source of bromineis molecular bromine (Br₂).183. The method of any one of embodiments 180 to 182, wherein the atleast one eighteenth base is pyridine.184. The method of any one of embodiments 179 to 183, wherein compound18:

or a salt thereof, is prepared by converting compound 19:

or a salt thereof, into compound 18, or a salt thereof.185. The method of embodiment 184, wherein the conversion of compound19, or a salt thereof, into compound 18, or a salt thereof, is performedin the presence of ethyl magnesium bromine (EtMgBr) and titanium(IV)isopropoxide (Ti(Oi-Pr)₄).186. A compound selected from:

and salts thereof,wherein:

X^(a) is selected from F, Cl, Br, I, and —OSO₂R;

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro;

X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I;

X^(d) is selected from F, Cl, Br, and I;

R³ is a monovalent nitrogen protecting group;

R⁴ is —SO₂R; and

-   -   R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl        optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        halo, or nitro; and wherein:

R¹ is hydrogen and R² is a monovalent nitrogen protecting group;

R¹ and R² are independently selected from monovalent nitrogen protectinggroups; or

R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and

wherein the compound is not:

or a salt thereof.187. The compound of embodiment 186, wherein each monovalent nitrogenprotecting group is independently selected from t-butyloxycarbonyl(Boc), benzyl (Bn), tetrahydropyranyl (THP),9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl,acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl(Ts).188. The compound of embodiment 186, wherein R¹ and R², together withthe atoms to which they are attached, form a nitrogen protecting groupselected from benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-thiodiglycoloyl amine, N-dithiasuccinimide, N-2,3-diphenylmaleimide,N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole,N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP),N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE),N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB),N-diphenylsilyldiethylene, N-5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, N-5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

General Syntheses

Compound I can be synthesized according to Scheme 1.

In some embodiments, the disclosure is directed to a process comprisingone or more of the following steps:

1) combining compound 45 with compound 46 to produce compound 47;

2) converting compound 47 into compound 48;

3) converting compound 48 into compound 40; and

4) combining compound 40 with compound 1 to produce Compound I.

In some embodiments, compound 45 is combined with compound 46 in thepresence of an alkoxide base to produce compound 47.

In some embodiments, compound 47 is converted into compound 48 in thepresence of an acid.

In some embodiments, compound 48 is converted into compound 40 in thepresence of a base.

In some embodiments, compound 40 is combined with compound 1 in thepresence of a base and optionally a metal catalyst to produce CompoundI.

In some embodiments, compound 40 is combined with compound 1 in thepresence of a copper catalyst to produce Compound I.

Compound I can also be synthesized according to Scheme 2.

In some embodiments, the disclosure is directed to a process comprisingone or more of the following steps:

1) combining compound 49 with compound 46 in the presence of an alkoxidebase to produce compound 50;

2) converting compound 50 into compound 48;

3) converting compound 48 into compound 40; and

4) combining compound 40 with compound 1 to produce Compound I.

In some embodiments, compound 49 is combined with compound 46 in thepresence of an alkoxide base to produce compound 50.

In some embodiments, compound 50 is converted into compound 48 in thepresence of aqueous base.

In some embodiments, compound 48 is converted into compound 40 in thepresence of a base.

In some embodiments, compound 40 is combined with compound 1 in thepresence of a base and optionally at least one metal catalyst to produceCompound I.

Compound I can also be synthesized according to Scheme 3.

In some embodiments, the disclosure is directed to a process comprisingone or more of the following steps:

1) combining compound 45 with compound 1 to produce compound 51;

2) combining compound 51 with compound 46 to produce compound 52;

3) converting compound 52 into compound 53; and

4) converting compound 53 into Compound I.

In some embodiments, compound 45 is combined with compound 1 in thepresence of a base and optionally at least one metal catalyst to producecompound 51.

In some embodiments, compound 51 is combined with compound 46 in thepresence of an alkoxide base to produce compound 52.

In some embodiments, compound 52 is converted into compound 53 in thepresence of an acid.

In some embodiments, compound 52 is converted into compound 53 in thepresence of palladium on carbon.

In some embodiments, compound 53 is converted into Compound 1 in thepresence of a base and optionally a metal catalyst.

Compound I was prepared according to the General Syntheses and SyntheticExamples disclosed herein.

In order that the disclosure described herein may be more fullyunderstood, the following general experimental procedures and examplesare set forth. It should be understood that these procedures andexamples are for illustrative purposes only and are not to be construedas limiting this disclosure in any manner.

General Experimental Procedures

The definitions of certain abbreviations for the Examples below aresummarized below:

Abbreviation Chemical Name Al₂O₃ aluminum oxide; alumina t-AmOKpotassium 2-methyl-2-butoxide; potassium tert-amylate; potassiumtert-amoxide t-AmOLi lithium 2-methyl-2-butoxide; lithium tert-amylate;lithium tert-amoxide t-AmONa sodium 2-methyl-2-butoxide; sodiumtert-amylate; sodium tert-amoxide Ba(OH)₂ barium hydroxide BH₃ boraneBH₃SMe₂ borane dimethylsulfide BH₃—THF borane-tetrahydrofuran Boct-butyloxycarbonyl Boc₂O di-tert-butyl dicarbonate; Boc anhydride Br₂bromine Bu₃N tributylamine nBu₄NH₄I tetra-n-butylammonium t-BuOKpotassium tert-butoxide t-BuXPhos2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl t-BuXPhos Pd G3[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II)methanesulfonate Cbz benzyloxycarbonyl Cbz—Cl benzyl chloroformateCs₂CO₃ cesium carbonate CsF cesium fluoride CuBr copper bromide CuIcopper iodide Cu(OTf)₂ copper(II) triflate CDI 1,1-carbonyl diimidazoleDABCO 1,4-diazabicyclo[2.2.2]octane DBU1,8-diazabicyclo[5.4.0]undec-7-ene DBN 1,5-diazabicyclo[4.3.0]non-5-eneDCM dichloromethane; methylene chloride DIAD diisopropylazodicarboxylate DIEA (DIPEA) N,N-diisopropylethylamine DMAN,N-dimethylacetamide DMCHDA N,N-dimethylcyclohexane-1,2-diamine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide EtMgBr ethylmagnesiumbromide Et₂O diethyl ether EtOH ethanol H₂ hydrogen gas H₂ water HATU1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HCl hydrochloric acid HCO₂H formic acid H₃PO₄phosphoric acid In(OTf)₃ indium(III) triflate InCl₃ indium(III) chlorideIPA isopropanol IPAc isopropyl acetate K₂CO₃ potassium carbonate KHCO₃potassium bicarbonate K₂HPO₄ potassium phosphate dibasic KOt-Bupotassium t-butoxide KOH potassium hydroxide K₃PO₄ Potassium phosphateLiAlH₄ lithium aluminum hydride Li₂CO₃ lithium carbonate LiOH lithiumhydroxide MeOH methanol MeCN (CH₃CN) acetonitrile 2-MeTHF2-methyltetrahydrofuran MgCl₂ magnesium chloride MTBD7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene MsCl methanesulfonylchloride; mesyl chloride MsOH methanesulfonic acid NaCN sodium cyanideNa₂CO₃ sodium carbonate NaH sodium hydride NaHCO₃ sodium bicarbonateNaN₃ sodium azide NaOH sodium hydroxide NiCl₂ nickel(II) chloride NMPN-methylpyrrolidone NsCl 4-nitrobenzenesulfonyl chloride; nosyl chlorideMTBE methyl tert-butyl ether MeTHF 2-methyltetrahydrofuran n-Oct₄NH₄Brtetra-n-octylammonium bromide Pd/Al₂O₃ palladium on alumina Pd/Cpalladium on carbon PdCl₂ palladium(II) chloride Pd₂(dba)₃bis(dibenzylideneacetone)palladium(0) Phth N-phthalimide PPh₃triphenylphosphine Pt/C platinum on carbon PtO₂ platinum dioxide; Adam’scatalyst Raney Ni (Ra-Ni) Raney Nickel Rh₂(OAc)₄ rhodium(II) acetatedimer; dirhodium tetraacetate SiO₂ silicon dioxide; silica SMB SimulatedMoving Bed chromatography TEA (Et₃N) triethylamine THF tetrahydrofuranTi(i-PrO)₄ titanium(IV) isopropoxide TsCl p-toluenesulfonyl chloride;tosyl chloride p-TsOH p-toluenesulfonic acid; tosylic acid ZnCl₂ zincchloride Zn(BH₄)₂ zinc borohydride

Reagents and starting materials were obtained from commercial sourcesunless otherwise stated and were used without purification.

SYNTHETIC EXAMPLES

Should the name of a compound conflict with the structure of thecompound anywhere in the present application, the structure supersedesthe name and is intended to be controlling.

Example 1: Synthesis of3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylicacid (6)

Step 1: Synthesis of [1,1′-bi(cyclopropan)]-1-ol (18)

A solution of methyl cyclopropanecarboxylate (109 g, 1.09 mol) in2-MeTHF (1.31 L) and titanium(IV) isopropoxide (71 mL, 240.6 mmol) wasstirred in a Morton flask then cooled to 18° C. Ethylmagnesium bromide(753 mL of 3 M, 2.259 mol) was added dropwise over 2 h to control thetemperature between 15 to 20° C. The mixture was stirred for another 2 hthen cooled to 5° C. and quenched drop-wise (slowly) with cold (˜5-10°C.) NaHSO₄ (1.31 L of 20% w/v, 2.182 mol) while keeping the temperaturebelow 10° C. The organic phase was isolated and the aqueous phase wasre-extracted with hexanes (500 mL). The aqueous phase was discarded. Theorganic phases were combined, washed with sat. aq. NaHCO₃(200 mL of 10%w/v, 238 mmol), dried over Na₂SO₄, and concentrated (30° C./˜40 torr) toafford 108.6 g of [1,1′-bi(cyclopropan)]-1-ol as a pale yellow liquid.The sample contained ˜8 wt % 2-MeTHF and 2 wt % iPrOH by ¹H NMR, so thecorrected yield of the desired product was 91%.

¹H NMR (400 MHz, Chloroform-d) δ 1.99 (s, 1H), 1.35 (tt, J=8.2, 5.1 Hz,1H), 1.22 (dd, J=9.0, 6.1 Hz, 1H), 0.70-0.65 (m, 2H), 0.52-0.45 (m, 2H),0.43-0.38 (m, 2H), 0.21-0.15 (m, 2H).

Step 2: Synthesis of 1-bromo-1,1′-bi(cyclopropane) (17)

A solution of Ph₃P (216 g, 824 mmol) in CH₂Cl₂ (770 mL) was cooled to−10° C. A solution of Br₂ (132 g, 42.6 mL, 824 mmol) in CH₂Cl₂ (154 mL)was added over 15 min. The mixture was stirred for an additional 15 minthen cooled further to −20° C. when pyridine (6.21 g, 6.35 mL, 78.5mmol) was added. A solution of [1,1′-bi(cyclopropan)]-1-ol (77.0 g, 785mmol), pyridine (65.2 g, 66.7 mL, 824 mmol), and DCM (385 mL) was addeddropwise while maintaining the temperature at about −15 to −20° C. Themixture was stirred at −20 to −10° C. for 45 min then heated to reflux(42° C.) until the reaction was completed (˜1 h). The mixture was cooledto ambient temperature and concentrated to remove most of the solvent.The mixture was slurried in hexanes (1 L), allowed to stand overnight,then filtered. The filter-cake was washed with hexanes (2×500-mL). Thenthe combined filtrate and washings were washed with aq HCl (392 mL of 1M, 392 mmol), then water (200 mL), then dried over Na₂SO₄, andconcentrated to afford 82.2 g (65% yield) of1-bromo-1,1′-bi(cyclopropane) as a yellow liquid.

¹H NMR (400 MHz, Chloroform-d) δ 5.30 (s, 1H), 1.61 (tt, J=8.2, 5.0 Hz,1H), 1.07-1.02 (m, 2H), 0.78-0.66 (m, 2H), 0.67-0.51 (m, 2H), 0.35-0.21(m, 2H).

Step 3: Synthesis of 1,1′-bi(cyclopropylidene) (16)

A solution of t-BuOK (62.7 g, 559 mmol) in DMSO (225 mL) was stirred atambient temperature. Then a solution of crude1-bromo-1-cyclopropyl-cyclopropane (75.0 g, 465.7 mmol) in DMSO (150 mL)was added dropwise while the temperature was maintained between 10 to25° C. with an ice-water bath. After 1 h the addition was completed andthe mixture was allowed to warm to ambient temperature. After 20 min¹HNMR showed that the reaction was reasonably clean and nearlycompleted.

After stirring overnight the product was isolated by flask-to-flaskvacuum-distillation with the condenser at −5° C. and the receiver in anice/i-PrOH bath. Vacuum was applied slowly from 100 to 40 torr. The potexternal temperature was increased from 70 to 80° C. The distillateslowly collected (20-30° C. head temperature) in the receiver to afford40.8 g of a colorless liquid that was a mixture of the desired product,t-BuOH and small amount of DMSO (1.0:1.1:0.15 molar ratio).

The product above was re-distilled using a 14/20 6-inch Vigreaux columnat atmospheric pressure under a nitrogen blanket. The condenser wascooled at 2° C. and the receiver was placed in an ice-water bath. Thedistillate collected (bp 60-62° C.) afforded 28.7 g as a colorlessliquid which was again a mixture of desired product, t-BuOH, and DMSO(1.0:1.8:0.15 molar ratio). The calculated yield (¹H NMR) was 10.0 g of1,1′-bi(cyclopropylidene).

The distillation was continued under reduced pressure (50-30 torr) whilethe external pot temperature was increased from ambient temperature to70° C. Additional distillate was collected in a cooled receiver(ice/i-PrOH) to collect an additional 6.9 g of 1,1′-bi(cyclopropylidene)containing trace amounts of t-BuOH and DMSO, for a total yield of 16.9 g(45%).

¹H NMR (400 MHz, Chloroform-d) δ 1.19 (s, 8H).

Step 4: Synthesis of ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (15)

A nitrogen-purged, 1-L jacketed reaction vessel was charged withRh(OAc)₂ (14.43 g, 32.64 mmol), 1,1′-bi(cyclopropylidene) (170 g, 2.122mol), and DCM (377.7 mL). The jacket was cooled at 0° C. (internaltemperature 0.6° C.). A metering pump was used to add ethyl2-diazoacetate (411.6 g, 379.4 mL, 3.607 mol) at 0.08 mL/min (4.8 mL/h).After 68 h (295 mL added), the addition was stopped (total ethyl2-diazoacetate added was ˜320 mL or 1.3 equivalents). The dark amberreaction mixture was warmed to 20° C. Celite was added (29 g; 2 g/gcatalyst) and the reaction mixture was allowed to stand overnight.

A portion of the reaction mixture was filtered using a Celite-packedbed. A DCM-packed SiO₂ (80 g) bed was prepared. The remaining unfilteredsuspension was slurried with SiO₂ (40 g) and filtered using the SiO₂ bedunder vacuum. The flask/bed were washed with DCM (3×400-mL). TheCelite-filtrate and the SiO₂ filtrate/washings were combined andconcentrated to afford 409 g (116%) of a dark brown liquid.

A bed of SiO₂ (300 g) was packed with hexanes. The concentrated obtainedabove was dissolved in heptane/hexanes (˜300 mL). The resulting solutionwas loaded onto the packed SiO₂ bed using hexanes (400 mL). The columnwas eluted with 10% EtOAc/hexanes, collecting ˜400-mL fractions—theeluting solvent turned orange (brown band stayed on the SiO₂ bed):Fraction 1 orange; Fraction 2 yellow; Fraction 3 light yellow; Fraction4 yellow-tinted. Fractions 1-3 were combined and concentrated to afford341.6 g of ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (97% yield) asan orange liquid.

¹H NMR (400 MHz, Chloroform-d) δ 4.13 (q, J=7.2 Hz, 2H), 2.24 (s, 1H),1.24 (t, J=7.1 Hz, 3H), 1.08-0.94 (m, 4H), 0.90-0.82 (m, 2H), 0.78 (ddd,J=8.3, 5.1, 3.6 Hz, 2H).

Step 5: Synthesis of dispiro[2.0.2⁴.1³]heptan-7-ylmethanol (13)

To a slurry of LiAlH₄ (24 g, 616.0 mmol) in THF (750 mL) was slowlyadded a solution of ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (100g, 601.6 mmol) in THF (250 mL) and the mixture came to a gentle reflux.The reaction temperature was controlled with an ice-bath and additionrate. The addition took 90 min and the mixture was stirred at ambienttemperature for 16 hr. The mixture was chilled with an ice bath and thereaction was quenched with the addition of water (24 mL, 1.332 mol),followed by NaOH (24 mL of 2 M, 48.00 mmol), and then water (72 mL,3.997 mol). The slurry was filtered over Celite and the filtrate wasconcentrated in vacuo. The oil was diluted with 300 mL of DCM and driedover MgSO₄, filtered, and concentrated in vacuo affordingdispiro[2.0.2⁴.1³]heptan-7-ylmethanol (58.5 g, 78%) as a light yellowoil.

¹H NMR (400 MHz, Chloroform-d) δ 3.71 (d, J=6.7 Hz, 2H), 1.71 (t, J=6.7Hz, 1H), 1.51-1.39 (m, 1H), 0.93-0.81 (m, 4H), 0.71-0.61 (m, 2H),0.61-0.49 (m, 2H).

Step 6: Synthesis of 7-(bromomethyl)dispiro[2.0.2⁴.1³]heptane (12)

To a solution of Ph₃P (98.5 g, 375.5 mmol) in DCM (600 mL) at −15° C.was added dropwise a solution of Br₂ (59.6 g, 372.9 mmol) in DCM (100mL). The reaction mixture was stirred at −15° C. for 15 min then chilledto −30° C. To the mixture was added dropwise a solution ofdispiro[2.0.2⁴.1³]heptan-7-ylmethanol (43.2 g, 347.9 mmol) and pyridine(30 mL, 370.9 mmol) in DCM (100 mL) over 20 min. Following the addition,the reaction was stirred for 1 h at −5° C., at which time analysis by ¹HNMR showed complete reaction. The reaction mixture was concentrated invacuo (35° C./200 torr) until approximately 100 mL of slurry remained.The slurry was diluted with ˜500 mL of 10% Et₂O/hexane and the solid wasfiltered off. The filtrate was concentrated in vacuo affording moreprecipitate which was removed by filtration. The filtrate wasconcentrated again and the slurry was diluted with 250 mL 10%Et₂O/hexanes. The precipitate was removed by filtration and washed with50 mL of Et₂O. The filtrate was concentrated in vacuo to afford7-(bromomethyl)dispiro[2.0.2⁴.1³]heptane (65 g, 100%).

¹H NMR (400 MHz, Chloroform-d) δ 3.49 (d, J=7.5 Hz, 2H), 1.90 (t, J=7.5Hz, 1H), 1.02-0.91 (m, 5H), 0.70 (ddd, J=9.2, 5.1, 4.0 Hz, 2H), 0.54(dddd, J=8.6, 4.8, 3.7, 1.0 Hz, 2H).

The product was used in the next step without further purification.

Step 7: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetonitrile (11)

To a solution of 7-(bromomethyl)dispiro[2.0.2⁴.1³]heptane (65 g, 347.5mmol) in DMSO (400 mL) was added NaCN (17.5 g, 357.1 mmol). The redmixture was stirred at ambient temperature for 16 h. The reaction waspoured into Na₂CO₃ (1,000 mL) and extracted three times with Et₂O (500mL). The combined organic phases were washed with water (500 mL), brine(500 mL), dried over MgSO₄, filtered, and concentrated in vacuoaffording 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetonitrile (45.9 g, 99%) asa dark red oil that contained residual Et₂O and PPh₃O.

¹H NMR (400 MHz, Chloroform-d) δ 2.42 (d, J=6.6 Hz, 2H), 1.69 (t, J=6.6Hz, 1H), 1.03-0.88 (m, 4H), 0.78-0.68 (m, 2H), 0.64-0.55 (m, 2H).

Step 8: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (10)

To a solution of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetonitrile (45 g,337.9 mmol) in ethanol (300 mL) and water (100 mL) was added NaOH (100 gof 50% w/w, 1.250 mol). The mixture was stirred at 70° C. for 16 hr. Theethanol was removed in vacuo and the remaining aqueous phase was dilutedwith water (200 mL) and extracted two times with MTBE (400 mL). Theaqueous phase was acidified with 6 M HCl (220 mL, 1.320 mol) and thedark mixture was extracted two times with MTBE (400 mL). The organicphase was washed with brine (400 mL), dried over MgSO₄, filtered, andconcentrated in vacuo affording 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)aceticacid (31.8 g, 62%) as a dark yellow solid that contained MTBE and traceamount of PPh₃O.

¹H NMR (400 MHz, Chloroform-d) δ 2.44 (d, J=6.9 Hz, 2H), 1.67 (t, J=6.9Hz, 1H), 0.91 (ddd, J=9.0, 5.2, 3.9 Hz, 2H), 0.81 (dddd, J=8.9, 5.2,4.0, 0.6 Hz, 2H), 0.68 (ddd, J=8.9, 5.2, 3.8 Hz, 2H), 0.55-0.45 (m, 2H).

Step 9: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethan-1-ol (8)

To a solution of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (28.4 g,186.6 mmol) in THF (320 mL) was added LiAlH₄ (8.2 g, 210.5 mmol)(pellets). The mixture was stirred at ambient temperature for 16 h (¹HNMR showed complete reaction). The reaction was quenched with thecareful sequential addition of water (8.2 mL, 455.2 mmol), NaOH (8.2 mLof 15% w/w), then water (24.6 mL, 1.366 mol). To the slurry was addedMgSO₄, and the slurry was stirred at ambient temperature for 30 min. Thelight yellow precipitate was filtered off using Celite and washed withMTBE. The filtrate was concentrated in vacuo (35° C., 150 torr)affording 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethan-1-ol (24.3 g, 94%yield) as a yellow oil, which contained 9% MTBE.

¹H NMR (400 MHz, Chloroform-d) δ 3.62 (t, J=6.9 Hz, 2H), 1.68 (q, J=6.8Hz, 2H), 1.39 (t, J=6.6 Hz, 1H), 0.89-0.74 (m, 4H), 0.65 (ddd, J=8.0,4.7, 3.5 Hz, 2H), 0.53-0.44 (m, 2H).

Step 10: Synthesis of 1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(7)

DIAD (490 mL, 2.49 mol, 1.15 equiv) was added to a suspension of2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethan-1-ol (85 wt %, 345 g, 2.17 mol, 1equiv), 1-tert-butyl 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate(555.6 g, 2.17 mol, 1 equiv), and triphenylphosphine (654.6 g, 2.49 mol,1.15 equiv) in toluene (3 L). After stirring at 40° C. overnight, thereaction was diluted with heptanes (1.2 L) and cooled to 20° C., over 60min, allowing the bulk of the triphenylphosphine oxide-DIAD complex tocrystallize out. Once at ambient temperature, the mixture was filtered,and the cake was washed with heptane (1.5 L) and suction dried. Thefiltrate was concentrated under reduced pressure to give crude1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylateas a viscous yellow oil (1.2 kg). The residue was purified by flashcolumn chromatography, eluting with 20% ethyl acetate in hexanes. Thecolorless oil was diluted with heptanes (200 mL) and stirred for ˜30 minat 0° C. The resulting white solid was filtered to give 1-(tert-butyl)4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(603.7 g, 74% yield, >95% purity).

¹H NMR (300 MHz, CDCl₃) δ 8.31 (s, 1H), 4.37-4.26 (m, 4H), 1.92 (d,J=6.9 Hz, 2H), 1.64 (s, 9H), 1.36 (t, 1H), 1.32 (t, J=4.2 Hz, 3H),0.86-0.82 (m, 4H), 0.64-0.60

(m, 2H), 0.49-0.46 (m, 2H).

Mass Spectrum (positive mode): m/z=377.3 [M+H]⁺.

Step 11: Synthesis of3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylicacid (6)

A 45% solution of potassium hydroxide in water (760 mL, 8.8 mol, 10.0equiv) was added in portions maintaining the internal temperature at<50° C. to a heated solution (40° C.) of 1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(330 g, 877 mmol, 1.0 equiv) in methanol (1 L). The reaction was stirredovernight at 50° C., at which point LCMS indicated the reaction wascomplete. The reaction was partially concentrated under reduced pressureto remove most of the methanol. The resulting solution was diluted withwater (1.65 L) and 2-MeTHF (1 L). The layers were shaken vigorously andseparated. The aqueous layer was washed again with 2-MeTHF (660 mL). Theaqueous layer was cooled to 5° C. and adjusted to pH 1 with 6M aqueousHCl (2.24 L) portionwise, maintaining the internal temperature between10 and 30° C. The product began to crystallize close to pH 7 and wasaccompanied with strong off-gassing. The resulting suspension wasdiluted with 2-MeTHF (2.7 L) and the product was allowed to dissolveinto the organic layer. Stirring was stopped and the layers wereseparated. The aqueous layer was re-extracted with 2-MeTHF (660 mL). Thecombined organic layers were washed with saturated brine (660 mL), driedover sodium sulfate, and filtered. The filtrate was concentrated underreduced pressure at 50° C. Heptanes (2 L) were added and the mixture waspartially concentrated under reduced pressure to remove most of the2-MeTHF. The mixture was stirred and cooled to room temperature. Theresulting solid was filtered and washed with heptanes (660 mL). Theproduct was dried under vacuum at 35° C. overnight to give3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylicacid (200.2 g, 92% yield, >99% purity) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 4.13 (t, J=13.0 Hz, 2H), 1.74(t, J=6.9 Hz, 2H), 1.41 (t, 1H), 0.83-0.77 (m, 4H), 0.62-0.57 (m, 2H),0.45-0.41 (m, 2H).

Mass Spectrum (positive mode): m/z=497.2 [2M+H]⁺.

Example 2: Alternative Synthesis of3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-H-pyrazole-4-carboxylic acid(6)

Step 1: Synthesis of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (24)

55% w/w hydrazine hydrate (29 mL, 515 mmol, 1.03 equiv) was addeddropwise to a solution of diethyl 2-(ethoxymethylene)propanedioate (108g, 500 mmol, 1 equiv) in ethanol (0.45 L). The resulting mixture washeated to reflux for 20 h, after which HPLC indicated complete reaction.The mixture was a slurry upon cooling to ambient temperature. The solidwas collected by filtration, washed with EtOH (2×100 mL), and dried in avacuum oven at 40° C. to afford 46 g (60%) of ethyl3-hydroxy-1H-pyrazole-4-carboxylate as an off-white solid.

Step 2: Synthesis of ethyl3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (23)

2,3-Dihydropyran (18 mL, 197.2 mmol, 1.03 equiv) was added to a solutionof ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (30 g, 192 mmol, 1 equiv)in acetonitrile (180 mL) and the resulting mixture was cooled at 0° C.p-Toluenesulfonic acid hydrate (1.26 g, 6.6 mmol, 0.035 equiv) was addedas a solid in one portion. After 2 h the mixture was allowed to warm to10° C. After 2 h, HPLC indicated complete conversion. The solid wascollected by filtration, washed with acetonitrile (2×35 mL), and driedin a vacuum oven at 40° C. to give ethyl3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (39.2g, 85%) as an off-white solid.

Step 3: Synthesis of ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate(21)

A mixture of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethyl methanesulfonate(9.2 g, 43.2 mmol, 1.04 equiv) and ethyl3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (10 g,41.6 mmol, 1 equiv) in DMF (50 mL) was stirred at room temperature. Then1,1,3,3-tetramethylguanidine (5.7 mL, 45.7 mmol, 1.1 equiv) was added,and the mixture was heated at 60° C. After heating for 12 h, HPLC showedcomplete reaction. 100 mL of water was added followed by 75 mL of ethylacetate. The phases were separated, and the organic layer was washedwith 25 ml of water. The organic layer was filtered, concentrated, anddried in a vacuum oven at 40° C. to give ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate(14.3 g) as a light yellow solid, which was used without furtherpurification.

Step 4: Synthesis of ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate(20)

A solution of ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate(7.15 g, 19.7 mmol, 1 equiv) in 4N HCl in 1,4-dioxane (138 mL, 572 mmol,29 equiv) was stirred at room temperature. A precipitate started formingafter about 30 min stirring. After 1 h, heptane (75 mL) was added andthe solid was collected by filtration, washed with heptane (2×10 mL),and dried in a vacuum oven at 40° C. to afford ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate(4.03 g) as a light yellow solid, which was used subsequently.

Step 5: Synthesis of3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylicacid (6)

45% Aqueous potassium hydroxide solution (6 g, 106 mmol, 10 equiv) wasadded to a solution of ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate(4.03 g, 14.5 mmol, 1.0 equiv) in methanol (12 mL) and the mixture wasstirred at 45° C. for 20 h. Water (20 mL) and 2-methyltetrahydrofuran(18 mL) were added and the layers were separated. The water layer waswashed with 2-methyltetrahydrofuran (8 mL) and adjusted to pH 1 with 6 NHCl. 2-Methyltetrahydrofuran (35 mL) was added and the layers wereseparated. The water phase was washed with 2-methyltetrahydrofuran (20mL). The organic layers were combined and washed with brine (10 mL),dried over sodium sulfate, and concentrated under reduced pressure togive3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylicacid as a white solid (2.73 g, 95.3% purity, 48% yield over 3 steps from2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethyl methanesulfonate).

Example 3: Alternative Synthesis ofdispiro[2.0.2⁴.1³]heptane-7-carboxylic acid (14)

Step 1: Synthesis of ethyl 2-cyclopropylideneacetate (26)

(1-Ethoxycyclopropoxy)trimethylsilane (200 g, 1147 mmol, 1.1 equiv) wasadded to a 3000 mL round-bottomed flask equipped with a magnetic stirbar. Then methanol (600 mL) was added and the resulting solution wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure (water bath at 25° C.). The oil that remained wasdissolved in tetraethylene glycol dimethyl ether (700 mL) with amagnetic stir bar. Then benzoic acid (28 g, 229 mmol, 0.22 equiv) wasadded and the resulting mixture was heated to 100° C. (heat block).Ethyl (triphenylphosphoranylidene) acetate (360 g, 1033 mmol, 1.0 equiv)was dissolved in dichloromethane (550 mL) in a 1000 mL addition funneland added dropwise to the above solution of cyclopropanone over a 2 htime period. After the addition, the switch of addition funnel wasclosed to collect condensed dichloromethane. The resulting mixture washeated at 100° C. for another h and then cooled to room temperature.Then the reaction mixture was purified by fractional distillation at0.54 Torr between 83-100° C. (cooling temperature of fluid in condenserwas at −6° C., all distillate under this condition was identified as theproduct) to give a total of crude ethyl 2-cyclopropylideneacetate(164.19 g, 61% purity by Q-NMR). The crude ethyl2-cyclopropylideneacetate was dissolved in pentane (400 mL), washed withice cold saturated sodium carbonate solution (100 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure (water bathat 25° C.) to give ethyl 2-cyclopropylideneacetate (92.52 g, 80% purityby Q-NMR, 57% yield) as a colorless liquid

¹H NMR (300 MHz, CDCl₃) δ 6.23 (t, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz,2H), 1.49-1.42 (m, 2H), 1.33-1.20 (m, 5H).

Mass Spectrum (positive mode): m/z=125.8 [M]⁺.

Step 2: Synthesis of ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (15)

Cyclopropyl(diphenyl)sulfonium (tetrafluoroborate) (95%, 265 g, 800mmol, 1.01 equiv) was dissolved in non-anhydrous dimethyl sulfoxide(4000 mL) in a 22 L round-bottomed flask equipped with an overheadstirrer. Room temperature water was added to the secondary container.Ethyl 2-cyclopropylideneacetate (79% purity by Q-NMR, 33.75 g; 80%purity by Q-NMR, 92.52 g, 793 mmol, 1.0 equiv) was added, followed bycesium hydroxide hydrate (containing about 10% H₂O, 133 g, 800 mmol,1.01 equiv) in one portion. At 120 min, ice was added to the secondarycontainer and the reaction was diluted with ice cold methyl tert-butylether (8 L). Ice cold saturated ammonium chloride solution (6 L) wasadded slowly while keeping the temperature below 25° C. The aqueouslayer was extracted with methyl tert-butyl ether (4 L×3), and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure (water bath at 25° C.) to give atotal of crude ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (316.67 g)as a pale yellow liquid.

Crude ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate with 17% ethyl2-cyclopropylideneacetate (68.17 g, ˜170.7 mmol, 1.0 equiv) wasdissolved in non-anhydrous dimethyl sulfoxide (300 mL) at roomtemperature. Cyclopropyl(diphenyl)sulfonium (tetrafluoroborate) (95%,19.2 g, 58 mmol, 0.34 equiv) was added, followed by cesium hydroxidehydrate (containing about 10% H₂O, 9.7 g, 58 mmol, 0.34 equiv) in oneportion. At 120 min, the reaction was diluted with methyl tert-butylether (800 mL). The DMSO layer was separated and cooled to 0° C. with anice bath. The MTBE layer was washed with saturated ammonium chloridesolution (650 mL). This aqueous layer was separated and slowly added tothe above DMSO mixture. The resulting aqueous layer was extracted withmethyl tert-butyl ether (800 mL), and the combined organic layers weredried over sodium sulfate, filtered, and concentrated under reducedpressure (water bath at 25° C.) to give crude ethyldispiro[2.0.2⁴.1³]heptane-7-carboxylate. (Another batch (204.51 g ofcrude ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate with 17% ethyl2-cyclopropylideneacetate used) of this reaction was processed in samemanner, and both batches were combined for purification. Then thiscombined mixture was purified by fractional distillation at 0.68 Torrbetween 68-120° C. (cooling temperature of fluid in condenser was at −6°C., all distillate under this condition was identified as the product)to give crude ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (83.32 g,65% purity by Q-NMR, 47% yield) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 6.23 (t, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz,2H), 1.49-1.42 (m, 2H), 1.33-1.20 (m, 5H).

Mass Spectrum (positive mode): m/z=165.1 [M−H]⁺.

Step 3: Synthesis of dispiro[2.0.2⁴.1³]heptane-7-carboxylic acid (14)

To a crude mixture of ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (5.0g, 30.0 mmol, 1.0 equiv) and diphenyl sulfide (6.24 g) in methanol/THF(8:1, 126 mL) was added lithium hydroxide (0.72 g, 30.0 mmol, 1.0 equiv)and a solution of sodium hydroxide (21.0 g, 525.0 mmol, 17.5 equiv) inwater (30 mL). The resulting mixture was stirred at 40° C. overnight.The solvents were removed under reduced pressure, then the residue wasdissolved in water (80 mL) and washed with methyl tert-butyl ether (80mL). The pH of the aqueous layer was adjusted to 2 using 5N HCl (˜110mL). The precipitate was collected by suction filtration and dried toconstant weight to give dispiro[2.0.2⁴.1³]heptane-7-carboxylic acid(2.98 g, 72% yield, >95% purity) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 2.26 (s, 1H), 1.11-1.02 (m, 4H), 0.90-0.80 (m,4H).

Mass Spectrum (positive mode): m/z=137.0 [M−H]⁺.

Example 4: Alternative Synthesis of2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (10)

Step 1: Synthesis of dispiro[2.0.2⁴.1³]heptane-7-carboxylic acid (14)

Sodium hydroxide (21.5 g, 542 mmol, 2.0 equiv) was added to a solutionof ethyl dispiro[2.0.2⁴.1³]heptane-7-carboxylate (45.0 g, 271 mmol, 1equiv) in a 4:1 mixture of methanol and water (500 mL) and stirred at55° C. for 4 h. LC-MS indicated the reaction was complete. Most ofsolvents were removed under reduced pressure, then the residue wassuspended in water (100 mL) and the pH was adjusted to 2 using 5N HCl.The precipitate that formed was collected by suction filtration anddried to constant weight to give dispiro[2.0.2⁴.1³]heptane-7-carboxylicacid (31 g, 85% yield, >95% purity) as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ 2.25 (s, 1H), 1.05 (m, 4H), 0.88-0.96 (m, 4H).

Mass Spectrum (positive mode): m/z=136.9 [M−H]⁺.

Step 2: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (10)

Thionyl chloride (176 mL, 2.4 mol, 9.6 equiv) was added todispiro[2.0.2⁴.1³]heptane-7-carboxylic acid (35 g, 251 mmol, 1.0 equiv),and the resulting solution was heated at 60° C. for two h. The reactionwas cooled to room temperature and concentrated under reduced pressure,and then azeotroped with toluene (2×50 mL) until all the thionylchloride was removed. The residue was diluted with anhydrousacetonitrile (3 L). Trimethylsilyl diazomethane (2M in hexanes, 190 mL,380 mmol, 1.5 equiv) was added over 5 min. After stirring for 2 h,silver acetate (64 g, 380 mmol, 1.5 equiv), triethylamine (70 mL, 502mmol, 2.0 equiv) and water (200 mL) were sequentially added. Afterstirring overnight, the reaction was filtered through a 2 inch pad ofCelite, which was rinsed with acetonitrile (100 mL). The combinedfiltrates were concentrated under reduced pressure to remove most of theacetonitrile. The resulting semi solid was diluted with 1N HCl (300 mL)and dichloromethane (300 mL). The mixture was filtered again throughCelite (1 inch pad), which was washed with additional dichloromethane(100 mL). The layers were separated and the organic layer was dried oversodium sulfate and concentrated under reduced pressure to give2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (28 g, 78% yield, 85%purity by GC-MS) as a yellow solid (containing ˜2.3% ofdispiro[2.0.2⁴.1³]heptane-7-carboxylic acid).

¹H NMR (400 MHz, Chloroform-d) δ 2.44 (d, J=6.9 Hz, 2H), 1.67 (t, J=6.9Hz, 1H), 0.91 (ddd, J=9.0, 5.2, 3.9 Hz, 2H), 0.81 (dddd, J=8.9, 5.2,4.0, 0.6 Hz, 2H), 0.68 (ddd, J=8.9, 5.2, 3.8 Hz, 2H), 0.55-0.45 (m, 2H).

Example 5: Alternative Synthesis of2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (10)

Step 1: Synthesis of ethyl2-(dispiro[2.0.2⁴.1³]heptan-7-yl)-2-oxoacetate (28)

A solution of ethyl 3-diazo-2-oxopropionate (16.2 g, 125 mmol, 2.0equiv) in dichloromethane (˜48 mL; total volume of solution was 60 mL)was added to a suspension of rhodium octanoate dimer (0.78 g, 1 mmol,0.016 equiv) and 1,1′-bi(cyclopropylidene) (5 g, 62.5 mmol, 1 equiv) indichloromethane (10 mL) at 0° C. by a syringe pump at 0.04 mL/min over24 h, keeping the needle tip under the solvent surface. After 24 h,¹H-NMR analysis showed 80% conversion of starting material (including˜10% of homo-coupling by-products). The reaction mixture was allowed towarm up to room temperature, and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography,eluting with a gradient of 0 to 30% ethyl acetate in heptanes (RediSep2×220 g) to give ethyl 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)-2-oxoacetate(7.1 g, 58% yield, >95% purity by ¹HNMR) as a light-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 4.28 (q, J=7.2 Hz, 2H), 3.24 (s, 1H), 1.35 (t,J=7.2 Hz, 3H), 1.15-1.09 (m, 2H), 1.01-0.95 (m, 2H), 0.92-0.80 (m, 4H).

Mass spectrum (positive mode): m/z=195.1 [M+H]⁺.

Step 2: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (10)

Ethyl 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)-2-oxoacetate (5 g, 25.7 mmol,1.0 equiv) was added dropwise to a solution of hydrazine hydrate (50-60%in water, 4.95 g, 77 mmol, 3.0 equiv) and water (5 mL) at −20° C. Thereaction mixture became a loose solid after addition. The mixture waswarmed to room temperature over 30 min and heated to 80° C. for 5 min.After the reaction mixture was cooled to room temperature, potassiumhydroxide (3.6 g, 64.4 mmol, 2.5 equiv) was added in three portionswhile the reaction mixture became a solution. The reaction was stirredat 80° C. for 16 h, after which GC-MS indicated the reaction wascomplete. The reaction mixture was cooled to room temperature, dilutedwith water (15 mL), and washed with diethyl ether (30 mL). The aqueouslayer was adjusted to pH 1 with concentrated HCl (˜6 mL). The aqueouslayer was extracted with toluene (4×50 mL). The combined organic layerwas washed with brine (50 mL), dried over sodium sulfate, andconcentrated under reduced pressure to give2-(dispiro[2.0.2⁴.1³]heptan-7-yl)acetic acid (3.2 g, 82% yield, 94%purity by ¹HNMR and GC-MS) as a light yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 2.44 (d, J=6.9 Hz, 1H), 1.63 (t, 1H),0.91-0.88 (m, 2H), 0.82-0.80 (m, 2H), 0.68 (m, 2H), 0.52 (m, 2H).

Mass Spectrum (positive mode): m/z=151.1 [M−H]⁺.

Example 6: Alternative Synthesis of 1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(7)

Step 1: Synthesis of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethylmethanesulfonate (22)

A mixture of 2-(dispiro[2.0.2⁴.1³]heptan-7-yl)-ethan-1-ol (20 g, 144.6mmol, 1 equiv) and triethylamine (26.1 mL, 185.8 mmol; 1.28 equiv) in2-MeTHF (160 mL) was cooled at 0° C. A solution of MsCl (15.1 mL, 193.7mmol; 1.34 equiv) in 2-MeTHF (90 mL) was added dropwise over 1 h whilemaintaining the reaction temperature at 0° C. After the addition wascompleted, the mixture was stirred at 0° C. for an additional 1 h. Themixture was allowed to warm to ambient temperature. The reaction mixturewas quenched with water (80 mL) and the phases were separated. Theorganic phase was washed with saturated aqueous NaHCO₃(80 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was vacuum-dried to afford2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethyl methanesulfonate (33.1 g) as abrown solid, which was used subsequently.

Step 2: Synthesis of 1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(7)

A mixture of 1-tert-butyl 4-ethyl3-hydroxy-1H-pyrazole-1,4-dicarboxylate (38.7 g, 151.2 mmol, 1 equiv),2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethyl methanesulfonate (33.1 g, 152.7mmol; 1.01 equiv), and Cs₂CO₃ (55.1 g, 169.3 mmol; 1.12 equiv) in DMF(180 mL) was heated at 50° C. for 24 h. After cooling to roomtemperature, the reaction mixture was diluted with water (360 mL) and2-MeTHF (360 mL), and the phases were separated. The aqueous phase wasextracted with 2-MeTHF (2×150 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography system, eluting with agradient of 0 to 35% ethyl acetate in heptanes (RediSep 220 g) to givecompound 1-(tert-butyl) 4-ethyl3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate(34.3 g, 67% yield over 2 steps from2-(dispiro[2.0.2⁴.1³]heptan-7-yl)-ethan-1-ol, 97% purity) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 4.35 (t, J=8.0 Hz, 2H), 4.31 (q,J=8.0 Hz, 2H), 1.93 (q, J=8.0 Hz, 2H), 1.63 (s, 9H), 1.48 (t, J=6.4 Hz,1H), 1.35 (t, J=8.0 Hz, 3H), 0.90-0.78 (m, 4H), 0.67-0.62 (m, 2H),0.50-0.47 (m, 2H).

Mass spectrum (positive mode): m/z=377.2 [M+H]⁺.

Example 7: Synthesis of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide(49)

Step 1: Preparation of(S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (4)

Racemic 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one wasdissolved in 80 g/L+/−8 g/L in MeOH/ACN 70/30 v/v (target 80+/−2 g/L)and separated on Chiralpak AD 20 μm as the stationary phase usingMeOH/ACN 70/30 v/v as the mobile phase.(S)-3-(2-Methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one is Peak 2.Optional recrystallization of(S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one:(S)-3-(2-Methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (9.5 kg, 1.0equiv) was stirred in isopropanol (76 L, 8 vol) then heated to >70° C.to dissolve the solid. The mixture was then cooled to 20° C. over 4-5 h,the solid isolated by filtration, and the cake washed with isopropanol(4.75 L, 0.5 vol) and pulled dry. The material was dried under vacuum toafford (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one in 90%recovery.

Step 2: Synthesis of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

A suspension of Raney Nickel 2400 (77 wt %, 2.8 kg) was allowed tosettle for 2 days. The standing liquid was decanted to waste and theremaining catalyst was charged to a reactor with the aide of water (2.6kg), then degassed with N₂. In a second reactor, a mixture of(S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (13.9 kg) andEtOH (170.8 kg) was heated to 30° C., then degassed with N₂, thentransferred to the reactor containing Raney Nickel. The transfer wascompleted with the aid of an EtOH (29.8 kg) rinse. The mixture waspurged three times with nitrogen and purged three times with hydrogen.The contents of the reactor were heated to 60-65° C. and stirred underH₂ (4-8 psi) until the reaction was completed (18 h). The mixture wascooled to 15-20° C., then purged with nitrogen three times, thenfiltered through a pad of Celite (3.0 kg) wetted with EtOH (3.2 kg). Thereactor and Celite cake were washed with EtOH (2×14.0 kg). The filtratewas distilled to a final volume of approx. 25 L then heated to 45° C.MTBE (269.4 kg) was then charged maintaining a temperature of 48-50° C.and then distilled at ambient pressure at 48-55° C. to a final volume ofapprox. 30 L. Two further portions of MTBE (269.4 kg then 187.4 kg) weresequentially added then concentrated to approx. 30 L volume.

The contents of the reactor were seeded with(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (70.1 g) at 40° C.The seeded crystal slurry was cooled to 15° C. over a period of 3.5 h,then stirred for 16.5 h between 12-15° C. then filtered. The reactor andfilter cake were then washed with cold (−2 to −10° C.) MTBE (2×10 kg).The filter-cake was dried to a constant weight which afforded(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.4 kg; 88%) as awhite, crystalline solid.

Recrystallization of(S)-3-(3-Hydroxypropyl)-5,5-dimethylpyrrolidin-2-one: A mixture of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.3 kg) and DCM(28.2 kg) was stirred and heated to 25° C. for 2 h then transferred toanother reactor through an in-line filter (45 um). The initial reactorwas rinsed with DCM (6.8 kg) at 21° C. for 10 min then transferred tothe reactor through the in-line filter. MTBE (38.1 kg) was charged tothe solution at 25-30° C. then the mixture was distilled over a periodof 2.5 h at 35-52° C. at atmospheric pressure to a final volume ofapprox. 30 L. MTBE (38.2 kg) was charged to the reactor at 45-50° C. Theresulting suspension was distilled over a period of 3.25 h at 49-55° C.at atmospheric pressure to a final volume of approx. 30 L. The contentsof the reactor were cooled to 21° C. over a period of 2.5 h and stirredfor 16 h at 20° C. The suspension was filtered. The reactor and filtercake were rinsed with MTBE (7.7 kg, 0.0° C.). The filter cake was driedover a period of 2 days. Yield: 9.1 kg (88.3%) of an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H),1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H).

ESI-MS m/z calc. 171.12593, found 172.0 [M+1]+.

GCMS:100% (AUC).

Chiral HPLC: 100% (AUC).

Step 3: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2)

LiAlH₄ pellets (332.5 g, 8.760 mol, 1.50 equiv) were slowly added to areactor with 2-MeTHF (10.00 L, 10 vol) at 30-40° C. The mixture was thenheated to 75° C. A mixture of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840mol, 1.00 equiv) and 2-MeTHF (10.00 L, 10 vol) was prepared in aseparate reactor and heated to 65° C., which was then carefullytransferred to the reactor containing the LiAH₄ mixture over 2 h. Themixture was stirred at 70° C. until the reaction was complete (18-24 h)then cooled to 0-10° C. Water (400.0 mL, 1×LiAlH₄ wt) was then carefullyadded while maintaining the mixture temperature at <30° C. A solution ofaq 15% NaOH (400.0 mL, 1×LiAlH₄ wt) was then added followed by water(400.0 mL, 1×LiAlH₄ wt) while maintaining the mixture temperature at<30° C. The resulting mixture was then heated to 60° C. and held at thattemperature for at least 30 min. The mixture was cooled to 20-30° C.then Celite (200 grams, 20 wt %) was added. The mixture was thenfiltered through a pad of Celite. The reactor and filter cake wererinsed with 2-MeTHF (4.0 L, 4.0 vol). The filtrate was concentratedunder vacuum to afford pyrrolidine compound(S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (872 g; 94.95% yield) asa clear oil.

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 3.36 (t, J=6.3 Hz, 3H), 2.95(dd, J=10.6, 7.6 Hz, 1H), 2.40 (dd, J=10.6, 7.7 Hz, 1H), 2.12-1.97 (m,1H), 1.69 (dd, J=12.1, 8.2 Hz, 1H), 1.47-1.25 (m, 5H), 1.08 (s, 3H),1.02 (s, 3H).

Step 4: Synthesis of(S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

A mixture of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2325 g,14.8 mol) and 6-bromo-2-fluoropyridine-3-carboxamide (3400 g, 15.5 mol)in 2-methyltetrahydrofuran (23 L) was stirred, then potassium carbonate(2650 g, 19.2 mol) and deionized water (7 L) were added. The mixture wasstirred at <25° C. until the reaction was complete (≥16 h).

The aqueous phase was removed and the upper organic phase was washedwith water (7 L) and 2% aqueous sodium chloride (7 L). The organic layerwas concentrated under reduced pressure to about 19 L.2-Methyltetrahydrofuran was chased from the mixture by two sequentialadditions and concentrations of acetonitrile (2×20 L) followed bydistillation. To the remaining solution was added acetonitrile (20 L)and the reaction was warmed to 85° C. for 2 h and then cooled at 10°C./h to 25° C. The slurry was cooled to 10° C. and stirred for 4 h thenfiltered. The cake was rinsed two times with acetonitrile (2×3 L) thenthe solid was dried under vacuum to afford(S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamideas a crystalline white solid (3850 g, 73% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.34 (dd, J=7.7,1.0 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.39 (q,J=5.7 Hz, 2H), 3.29-3.12 (m, 2H), 2.19 (dt, J=10.9, 5.8 Hz, 1H), 1.92(dd, J=11.9, 5.7 Hz, 1H), 1.53 (s, 3H), 1.50 (s, 3H), 1.48-1.29 (m, 5H).

Step 5: Synthesis of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide(49)

A mixture of(S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide(2.65 kg, 7.4 mol), 2-methyltetrahydrofuran (16 L), and triethylamine(900 g, 8.88 mol) was stirred at 20° C., then methanesulfonyl chloride(933 g, 8.14 mol) was added over 2 h. The mixture was stirred at 20° C.until the reaction was completed (typically 16 h). The resulting mixturewas filtered and the filter cake was rinsed with tert-butyl methyl ether(2×4 L). The combined filtrates (containing the mesylate intermediate)were transferred to a reactor and diluted with dimethyl sulfoxide (16L). To the mixture was added phthalimide (1198 g, 8.14 mol). The mixturewas stirred until a solution was obtained, then potassium carbonate(1023 g, 7.4 mol) was added and the mixture was stirred and heated to70° C. until the reaction was completed (2 h). The mixture was cooled to20° C. and diluted with 2-methyltetrahydrofuran (16 L), followed by theaddition of deionized water (21 L). The phases were separated and theupper organic phase was washed with deionized water (10 L) and saturatedaqueous sodium chloride (2×1 L). The organic phase was diluted withtoluene (16 L) and concentrated under reduced pressure to approximately10 L volume. The solid was isolated by filtration and the filter cakewas rinsed with toluene (2×2 L). The resulting solid was dried to affordcompound(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamideas an off-white solid (3393 g, 6.99 mol, 94% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.80 (m, 4H), 7.80-7.71 (m, 1H),7.42-7.36 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.29-7.09 (m, 3H), 6.67 (d,J=7.7 Hz, 1H), 3.59 (t, J=6.9 Hz, 2H), 3.23 (t, J=10.4 Hz, 1H), 3.16(dd, J=10.2, 7.4 Hz, 1H), 2.30 (s, 2H), 2.28-2.13 (m, 1H), 1.90 (dd,J=12.0, 5.6 Hz, 1H), 1.71-1.53 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H),1.47-1.23 (m, 3H).

Example 8: Synthesis of(R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

The reactions in this example provide(R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide,because (S)-(−)-a-methylbenzylamine was used as a reagent.(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamidecan be obtained using the same reactions and (R)-(−)-a-methylbenzylamineas a reagent.

Step 1: Synthesis of tert-butyl(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)carbamate (37)

To a stirring solution of 3-tert-butoxycarbonylamino-propionic acid(30.0 g, 158.6 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (27.4 g, 190.3mmol) and 4-dimethylaminopyridine (31.03 g, 254.0 mmol) indichloromethane (600 mL) at 0° C. was dropwise added a solution ofN,N-dicyclohexylcarbodiimide (39.3 g, 190.3 mmol) in dichloromethane(300 mL). After the addition was complete, the reaction mixture wasallowed to warm up to room temperature and stirred for 16 h. Theprecipitated dicyclohexylurea was filtered off, and the filtrate waswashed with 5% aqueous potassium bisulfate solution (3×200 mL) followedby brine (100 mL) and dried over anhydrous magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was cooled to 0° C.Glacial acetic acid (91 mL, 1.59 mol) was slowly added, followed by aportionwise addition of sodium borohydride (15.0 g, 397.0 mmol). Afterthe addition was complete, the reaction mixture was allowed to warm upto room temperature and stirred for 18 h. The reaction mixture wasre-cooled to 0° C. and quenched with water (200 mL). The organic layerwas separated, washed with water (2×300 mL) followed by brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to afford crude2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione(49.05 g, 103%, contained ˜10% of unreacted2,2-dimethyl-[1,3]dioxane-4,6-dione) as an off-white solid. The crudeproduct was carried to the next step without further purification.

LCMS Method: Final purity was determined by reverse phase HPLC using aKinetex C18 column (50×3.0 mm) and a dual gradient run from 5-100%mobile phase B over 12 min. Mobile phase A=water (0.1% CF₃CO₂H). Mobilephase B=acetonitrile (0.1% CF₃CO₂H). Flow rate=1.5 mL/min, injectionvolume=10 μL, and column temperature=30° C.

¹H NMR (250 MHz, CDCl₃) δ (ppm): 4.62 (broad s, 1H), 3.74-3.72 (m, 1H),3.22-3.15 (m, 2H), 2.17-2.08 (m, 2H), 1.81 (s, 3H), 1.75 (s, 3H),1.70-1.66 (m, 2H), 1.43 (s, 9H).

ESI-MS m/z calc. 301.3, found 302.2 [M+1]+. Retention time: 3.87 min.

Step 2: Synthesis of ethyl5-((tert-butoxycarbonyl)amino)-2-methylenepentanoate (36)

To a stirring solution of2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione(23.7 g, 78.6 mmol) in anhydrous ethanol (850 mL) under nitrogenatmosphere was added N,N′-dimethylmethyleneiminium iodide (36.5 g, 197.0mmol). The reaction mixture was heated to 65° C. for 18 h. The reactionmixture was concentrated and the crude product was extracted with ethylacetate (400 mL). The organic layer was washed with saturated aqueoussodium bicarbonate solution (400 mL), 10% aqueous potassium bisulfate(400 mL), and brine (100 mL), then dried over anhydrous sodium sulfateand concentrated. The product was purified by silica gel columnchromatography using 0-15% hexanes-ethyl acetate to afford5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (14.76g, 73%) as a colorless oil.

¹H NMR (250 MHz, CDCl₃) δ (ppm): 6.17 (s, 1H), 5.56 (s, 1H), 4.60 (broads, 1H), 4.24-4.16 (q, J=7.1 Hz, 2H), 3.17-3.10 (m, 2H), 2.30-2.36 (m,2H), 1.72-1.60 (m, 2H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).

ESI-MS m/z calc. 257.3, found 258.7 [M+1]+. Retention time: 5.12 min.

Step 3: Synthesis of ethyl2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoate (35)

To a stirring solution of5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (16.95g, 65.87 mmol) and 2-nitropropane (29.4 g, 330.0 mmol) in anhydrousacetonitrile (250 mL) under nitrogen atmosphere was added1,8-diazabicyclo[5.4.0]undec-7-ene (12.03 g, 79.0 mmol), and thereaction mixture was heated to 90° C. for 2 h. The reaction mixture wasconcentrated and the residue was extracted with ethyl acetate (400 mL).The organic layer was washed with 5% aqueous potassium bisulfatesolution (2×300 mL) followed by brine (100 mL), dried over anhydroussodium sulfate, and concentrated. The product was purified by silica gelcolumn chromatography using 0-25% hexanes-acetone to afford2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acidethyl ester (20.65 g, 90%) as a yellow oil.

¹H NMR (250 MHz, CDCl₃) δ (ppm): 4.51 (broad s, 1H), 4.17-4.08 (q, J=7.1Hz, 2H), 3.13-3.08 (m, 2H), 2.45-2.29 (m, 2H), 2.17-2.04 (m, 1H),1.73-1.64 (m, 1H), 1.58-1.36 (m, 18H), 1.25 (t, J=7.1 Hz, 3H).

ESI-MS m/z calc. 346.4, found 347.3 [M+1]. Retention time: 5.65 min.

Step 4: Synthesis of2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid((f)-34)

To a mixture of2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acidethyl ester (5 g, 14.43 mmol) in ethanol (20 mL) under nitrogenatmosphere was added 10% w/v NaOH (7 mL, 17.50 mmol), and the reactionmixture was heated to 50° C. After 5 h an additional 0.7 mL of 10% w/vNaOH was added. After heating for an additional 2 h, LC showed completereaction. 20 mL of water was added to the reaction mixture and themixture was concentrated to remove EtOH. 15 mL of IPAc was added. Aftermixing, the layers were separated and the aqueous layer was made acidicwith 6 M HCl (pH 2-3). 20 ml of IPAc was added. After mixing, theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated to afford2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid.

The crude product from above was dissolved in 30 mL of IPAc.Dicyclohexylamine (2.6 mL, 13.05 mmol) was added dropwise via additionfunnel. Crystallization initiated upon stirring. After stirring theslurry for several h, the solid was collected by filtration and washedwith IPAc (2×7 mL). The salt was dried in a vacuum oven at 50° C. with aN₂ bleed to afford 6.37 g of2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic aciddicyclohexylammonium salt (88% for 2 steps).

The salt was then slurried in 40 mL of IPAc. 20 mL of 10% aq w/v citricacid was added. The mixture was stirred vigorously until all solidsdissolved. The layers were then separated and the organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated. 50 mLof heptane was added and the mixture was concentrated. 40 mL of heptanewas added to the solid and the slurry was stirred at ambienttemperature. After stirring the slurry for several hours, the solid wascollected by filtration and washed with heptane (2×8 mL). The productwas dried in a vacuum oven at 50° C. with a N₂ bleed to afford 3.27 g of2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid(71% overall for the process).

Step 5: Synthesis of(R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoicacid

Initial Crystallization: To a 100 mL flask containing2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoic acid(5 g, 15.705 mmol, 1 equiv) in CH₃CN (25 mL, 0.628 M, 5 Vols),(S)-(−)-a-methylbenzylamine (0.952 g, 1.012 mL, 7.852 mmol, 0.5 equiv)was added. Stirred at ambient temperature, the mixture initially turnedclear and then became a slurry within 5-10 min.

The mixture was heated to 75° C. and held at 71-75° C. for 1 h, thencooled to 60° C. and held at 60° C. for 1 h. Then the mixture was cooledto 50° C., and was seeded with −25 mg of(R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoicacid. The mixture became cloudy, and after 1 hr it was cooled to 40° C.,and the resulting slurry was held at 40° C. for 1 hr, then cooled toambient temperature and stirred overnight. The slurry was collected byfiltration, rinsed with ACN (3×3 mL), and dried under vacuum oven at 40°C. overnight with a N₂ bleed. 2.27 g was obtained (TY=3.45 g, 65%). Theenantiomer ratio was 95:5 [% (AUC)]. The mother liquor ratio was 26:74.

1^(st) Recrystallization: In a 50 mL of RBF, (1R)-1-phenylethanaminium2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate(2.22 g, 5.051 mmol, 1 equiv) in CH₃CN (15.54 mL, 0.325 M, 7 Vols).Mixture heated to 75° C., mixture became homogeneous at 66° C., hold at71-75° C. for 1 h. Then cool to 60° C., slurry formed. Hold at 60° C.for 1 h. Cool to 50° C. and hold for 1 h. Cool to 40° C. Hold at 40° C.for 1 hr and then cool to ambient stirring overnight. Solid wascollected by filtration and dried over the vacuum oven at 40° C. with N₂bleed overnight to afford 2.056 g of product as white solid (92%). Theenantiomer ratio was 97:3 [% (AUC)]. The mother liquor ratio was 25:75.

2^(nd) Recrystallization: To a 100 mL round-bottomed flask was added(1R)-1-phenylethanaminium2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate (2g, 4.55 mmol, 1 equiv) in CH₃CN (16 mL, 0.284 M, 8 Vols). The mixturewas heated to 75° C. The mixture became homogeneous at >66° C., then washeld at 71-75° C. for 1 h. The mixture was then allowed to cool to 65°C. A slurry formed and was held for 1 h. Then it was cooled to 60° C.and held for 1 h, then cooled to 55° C. and held for 1 h, then cooled to50° C. and held for 1 h, then cooled to 45° C. and held for 1 h, thencooled to ambient and stirred overnight. The solid was collected byfiltration and dried in a vacuum oven at 40° C. with a N₂ bleedovernight to afford 1.92 g of product as white solid (96%, 57% overall).The enantiomer ratio was 99:1 [% (AUC)]. The mother liquor ratio was53:47.

Step 6: Synthesis of tert-butyl(R)-(4-(hydroxymethyl)-6-methyl-6-nitroheptyl)carbamate

CDI (305.7 mg, 1.885 mmol) was added to a solution of(R)-2-[3-(tert-butoxycarbonylamino)propyl]-4-methyl-4-nitro-pentanoicacid (500 mg, 1.571 mmol) in THF (1.500 mL) at room temperature. Themixture was stirred at ambient temperature. CDI activation of carboxylicacid was checked using n-butylamine in ACN. UPLC was checked at 80 min,3 h, and 4 h.

This reaction mixture was then transferred over 15 min to a solution ofNaBH₄ (178.3 mg, 188.7 μL, 4.713 mmol) in a mixture of THF (1.000 mL)and H₂O (625.0 μL) at 0-5° C. The addition was exothermic. The mixturewas stirred for 90 min at ambient temperature. UPLC showed the startingmaterial was fully consumed.

EtOAc (2.5 mL) and aqueous citric acid (approximately 2.415 g, 1.450 mL,12.57 mmol) (in 2.5 mL of water) was added to quench the reaction. Thelayers were separated. The pH of the aqueous layer was 3. The organiclayer was dried over Na₂SO₄ and concentrated by rotary evaporation (80mbar, 20° C. bath temp.) MTBE (5 mL) was added to the crude product andwas washed with 1.5 mL of Sat. bicarb/water (1:1), at which point theaqueous layer pH was 5. The wash was repeated, at which point theaqueous layer pH became 7. The MTBE layer was dried over Na₂SO₄ andconcentrated by rotary evaporation (300-150 mbar, 20° C. bath temp.) andused for the next step reaction without further purification.

Step 7: Synthesis of(R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentyl4-methylbenzenesulfonate

To the mixture of (R)-tert-butyN-[5-hydroxy-4-(2-methyl-2-nitropropyl)pentyl]carbamate (480 mg, 1.577mmol, 1 equiv), triethylamine (0.319 g, 0.443 mL, 3.154 mmol, 2 equiv)and trimethylamine hydrochloride (0.154 g, 1.608 mmol, 1.02 equiv) in2-MeTHF (3.5 mL, 0.451 M, 7.292 Vols), was added p-toluenesulfonylchloride (0.451 g, 2.365 mmol, 1.5 equiv) at 0-5° C. The reaction wasstirred at this temperature for 1 h, then warmed to ambient temperatureand stirred at ambient temperature for another 3 h. By UPLC, thestarting material was fully consumed. The reaction mixture was washedwith water and brine, dried over Na₂SO₄, and concentrated. The crude waspurified by column chromatography eluting with EtOAc/Hexane.

Step 8: Synthesis of tert-butyl(R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

To the solution of (R)-tert-butylN-(6-methyl-4-{1[(4-methylbenzenesulfonyl)oxy]methyl}-6-nitroheptyl)carbamate(0.55 g, 1.103 mmol, 1 equiv) in MeTHF (9 mL, 0.123 M, 16.364 Vols) wasadded potassium carbonate (0.153 g, 1.103 mmol, 1 equiv) and Raneynickel (0.13 g, 1.103 mmol, 1 equiv). The mixture was degassed (vacuum)then purged with a hydrogen balloon (3 times). The reaction was heatedto 78° C. The reaction mixture was cooled to room temperature andfiltered through celite, and the cake was washed with MeTHF (50 mL). Thefiltered solution was washed with water, some product went to waterlayer (pH 5-6), the water layer was re-extracted with MeTHF. Thecombined MeTHF layer was dried over Na₂SO₄ and concentrated on rotovap.After drying under house vacuum overnight, 640 mg of crude product wasobtained as an oil and was used without further purification.

Step 9: Synthesis of(R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione

A method for preparing(R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione fromtert-butyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate is shownin the scheme above.

Step 10: Synthesis of(R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

In a 3 necked 1 L round bottom flask,(R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione(38.98 g, 136.1 mmol, 1.03 equiv), 6-bromo-2-fluoronicotinamide (28.91g, 132.0 mmol, 1 equiv), and MeCN (202 mL, 7 vol) were added followed byK₂CO₃ (−325 mesh, 21.16 g, 153.1 mmol, 1.16 equiv). The mixture washeated to 40° C. and the reaction was monitored by LC analysis. Thereaction went to completion after 17 h. The reaction mixture was cooleddown to ambient temperature. 300 mL (10.3 vol) of water was addedthrough an addition funnel to afford a slurry. The resulting solid wascollected by filtration. The solid was washed with water/MeCN (1/2, 2×40mL, 1.4 vol) then dried by vacuum oven at 45° C. to afford(R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide(56.5 g 88%).

Example 9: Synthesis of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(50)

Step 1: Synthesis of perfluorophenyl 6-fluoropyridine-2-sulfonate

To a solution of 2,3,4,5,6-pentafluorophenol (33.21 g, 180.4 mmol) iniPrOAc (175 mL) was added aq KHCO₃ (approximately 90.30 mL of 20% w/v,180.4 mmol). The mixture was stirred at ambient temperature for 10 min.A solution of 6-fluoropyridine-2-sulfonyl chloride (35.29 g, 180.4 mmol)in iPrOAc (25 mL) was then added while keeping the temperature below 20°C. The reaction mixture was allowed to stir at ambient temperature for 1hr to complete the reaction. The aqueous layer was removed, and theorganic layer was washed with water (50 mL), dried over Na₂SO₄, thenconcentrated by rotary evaporation to remove most of solvent andprecipitate a white solid. Heptane (70 mL) was added and the slurry wasstirred at ambient temperature. The solid was collected by filtration,rinsed with heptane (30 mL), and dried under vacuum to give 58.76 g ofperfluorophenyl 6-fluoropyridine-2-sulfonate as a white solid. Themother liquor was concentrated by rotary evaporation, then 1 mL(iPrOAc)/20 mL (Heptane) was added and stirred at ambient temperatureovernight. The resulting solid was collected and dried under vacuum ovenat ambient temperature overnight with a N₂ bleed to give 0.87 g as asecond crop. In total, 59.63 g (96% yield) of perfluorophenyl6-fluoropyridine-2-sulfonate was obtained.

¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (q, J=7.7 Hz, 1H), 8.20 (dd, J=7.5, 2.0Hz, 1H), 7.84 (dd, J=8.3, 2.2 Hz, 1H).

¹⁹F NMR (376 MHz, DMSO-d₆) δ −64.25 (s, 1F), −152.20-−152.69 (m, 2F),−154.84 (t, J=23.3 Hz, 2F), −161.00-−161.74 (m, 1F).

Step 2: Synthesis of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(50)

A solution of lithium tert-butoxide (1,905.13 g, 2.20 equiv, 20% w/w inTHF) was added to a mixture of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide(1,050 g, 1.00 equiv) and perfluorophenyl 6-fluoropyridine-2-sulfonate(890.93 g, 1.20 equiv) in 2-MeTHF (10.5 L, 10.0 vol), keeping theinternal temperature below −2° C. The mixture was stirred at −10° C.until the reaction was complete (typically 0.5 h). A solution of aq HCl(5.25 L, 5 vol, 1 N) was added while keeping the internal temperature<20° C. 2-MeTHF (5.0 L, 5 vol) was then added to the reactor at ambienttemperature and then the phases were allowed to separate. The loweraqueous layer was discarded. The organic phase was washed with water (5vol) then concentrated to 5 volumes under vacuum keeping the temperaturebelow 50° C. 2-MeTHF (10.0 L, 10 vol) was added and again the mixtureconcentrated to 5 volumes. 2-MeTHF (5 vol) was added and theheterogenous mixture was heated to 70° C. with agitation until completedissolution occurred. The mixture was then cooled linearly to 45° C.over 6 h then held at 45° C. for 6 h. The mixture was then cooled to 25°C. over 2 h then heptane (10.0 L, 10 vol) was added to the mixture over3 h. The mixture was drained from the reactor and the solids wereisolated. The reactor and filter cake were then washed twice with amixture of 2-MeTHF (2.0 L, 2 vol) and heptane (2.0 L, 2 vol). The solidswere dried under vacuum at 45° C. to afford(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide.

¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (s, 1H), 8.37 (q, J=7.8 Hz, 1H), 8.11(dd, J=7.4, 1.9 Hz, 1H), 7.95-7.88 (m, 2H), 7.88-7.81 (m, 2H), 7.59 (dd,J=8.1, 2.4 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 3.59 (t, J=6.8 Hz, 2H), 2.45(dd, J=8.8, 3.9 Hz, 2H), 2.17 (s, 1H), 1.87 (dd, J=11.9, 5.5 Hz, 1H),1.56 (dddd, J=22.3, 16.7, 8.9, 4.1 Hz, 2H), 1.47 (s, 3H), 1.44 (s, 3H),1.35 (t, J=12.1 Hz, 1H), 1.21 (ddd, J=13.3, 10.5, 5.4 Hz, 1H), 1.00(dtd, J=14.1, 9.4, 5.7 Hz, 1H).

Example 10: Synthesis of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(40)

Step 1: Alternative Synthesis of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(50)

6-Fluoropyridine-2-sulfonyl chloride (529 g, 340 mL, 2.71 mol) was addedto a solution of a 2:1 ratio of(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamidein toluene (1.20 kg, 2.26 mol; 91.2% potency) in 2-MeTHF (6.56 L; 6VolEq) at 0-5° C. then lithium 2-methylbutan-2-olate (t-OAmLi; 1.22 kgof 40% w/w, 1.67 L of 40% w/w, 5.19 mol; 2.3 equiv) was added whilemaintaining the reaction temperature between 5-10° C. After the additionwas completed, the reaction solution was stirred at 0-10° C. until thereaction is complete (HPLC shows <1% AUC(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamideremains). The reaction solution was advanced to the next step withoutany further processing.

Step 2: Synthesis of(S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoicacid

The reaction solution containing(S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamidefrom the preceding step was cooled and maintained below 10° C. when asolution of LiOH.H₂O (284 g, 6.77 mol; 3 equiv) in water (2.19 L; 2VolEq) was added. The biphasic mixture was stirred at 5-15° C. until thereaction was completed (about 2 h). While maintaining the reactiontemperature below 10° C., 2 M HCl (5.64 L, 11.3 mol; 5 equiv) was addeddropwise over ˜1 h. The pH of the aqueous phase was about 2. The phaseswere separated then the organic phase was concentrated to a minimumvolume removing most of the 2-MeTHF (40° C./150-70 torr). The reactionmixture was advanced to the next step without any further processing.

Step 3: Synthesis of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(48)

The concentrate containing(S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoicacid from the preceding step was diluted with CH₃CN (6.56 L; 6 VolEq)and water (3.83 L; 2 VolEq) then oxalic acid (508 g, 5.64 mol; 2.5equiv) was added and the resultant solution was heated at 60° C. untilthe reaction was complete (about at least 4 h). The solution was cooledto 0-10° C. then a solution of K₂CO₃ (2.18 kg, 15.8 mol; 7 equiv) inwater (3.83 L; 3.5 VolEq) was added dropwise while maintaining thereaction temperature below 10° C. The solid was collected by filtration.The damp filter-cake was washed consecutively with water (2×2.2 L; 2VolEq) and then i-PrOH (2×600 mL; 0.5 VolEq), air-dried with suction,and vacuum-dried (50° C./30 torr) to afford(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(959 g; 83% for 3 steps; >98% AUC) as a fine, white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (q, J=7.9 Hz, 1H), 7.83 (dd, J=7.5, 2.2Hz, 1H), 7.67 (s, 3H), 7.39 (d, J=7.6 Hz, 1H), 7.23 (dd, J=8.2, 2.4 Hz,1H), 6.58 (d, J=7.6 Hz, 1H), 3.20-2.99 (m, 2H), 2.81 (td, J=7.2, 4.7 Hz,2H), 2.08 (dh, J=15.3, 7.0 Hz, 1H), 1.84 (dd, J=11.8, 5.7 Hz, 1H), 1.54(q, J=7.6 Hz, 2H), 1.48 (s, 3H), 1.47 (s, 3H), 1.37 (t, J=11.9 Hz, 1H),1.26 (ddd, J=29.1, 13.8, 7.4 Hz, 2H).

Step 4: Synthesis of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(40)

A mixture of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(950 g, 1.85 mol) and Na₂CO₃ (392 g, 3.69 mol; 2 equiv) in DMSO (7.60 L;8 VolEq) was heated at 85° C. until the reaction was completed (˜6 h).The suspension was cooled to <15° C. and diluted with MeTHF (19.0 L; 20VolEq). Water (13.3 L) was added slowly while maintaining the reactiontemperature <15° C. While maintaining the reaction temperature <15° C.,2 M HCl (4.62 L, 9.24 mol; 5 equiv) was added (pH ˜2). The phases wereseparated and the organic phase was washed twice with water (9.50 L; 10VolEq) containing NaCl (190 g; 2 wt %). The organic phase wasconcentrated to a minimum volume (45° C./180 torr) and chased withi-PrOAc (2-3×500 mL) to remove the MeTHF. The concentrate was backfilledwith i-PrOAc (3.800 L; 4 VolEq) and agitated at 45° C. untilcrystallization occurred. (The mixture may be seeded with(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trioneif necessary). The suspension was aged with agitation for at least 30min and then allowed to cool to 20° C. After aging at 20° C. for atleast 2 h, the solid was collected by filtration. The filter-cake waswashed with 1:1 i-PrOAc/MTBE (500-mL), air-dried with suction, andvacuum-dried (40-55° C./<100 torr/N₂ bleed) to afford(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.0.8i-PrOAc (830 g; 78% yield corrected for i-PrOAc solvate) as a whitepowder with a slight yellow tint.

A second crop was obtained by concentrating the filtrate to −400 mLtotal volume. The mixture was then seeded and aged at 15-20° C. Thesolid was collected by filtration. The filter-cake was washedsuccessively with 1:1 i-PrOAc/MTBE (200 mL) and MTBE (100 mL), air-driedwith suction, and vacuum-dried (55° C./<100 torr/N₂ bleed) to afford(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.0.67i-PrOAc (113 g; 11% corrected yield) as a pale yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.66 (d, J=7.9 Hz, 1H),7.54 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.9 Hz,1H), 6.56 (d, J=8.4 Hz, 1H), 4.99 (hept, J=6.3 Hz, 1H), 4.57 (d, J=8.8Hz, 1H), 4.02-3.85 (m, 1H), 3.27-3.09 (m, 2H), 2.96 (t, J=10.2 Hz, 1H),2.35 (p, J=9.5 Hz, 1H), 2.02 (s, 3H), 1.95 (dd, J=12.1, 6.7 Hz, 1H),1.72-1.59 (m, 6H), 1.58 (s, 3H), 1.55 (s, 3H), 1.43 (d, J=40.1 Hz, 1H),1.23 (d, J=6.3 Hz, 5H).

Example 11: Synthesis of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(40)

A mixture of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(40.2 g, 78.2 mmol) and K₂CO₃ (−325 mesh, 27.0 g, 195.5 mmol; 2.5 equiv)in DMSO (0.4 L; 10 VolEq) was heated at 70° C. until the reaction wascompleted. The suspension was cooled to <15° C. and diluted with IPAc(0.3 L; 7.5 VolEq). While maintaining the reaction temperature <15° C.,1 M HCl (0.41 L, 406.8 mmol; 4.3 equiv) was added (pH ˜2).

After aging at 20° C. for at least 2 h, the solid was collected byfiltration. The filter-cake was washed with water (4×50-mL) followed byIPAc (2×75 mL), air-dried with suction, and vacuum-dried (45° C./<100torr/N₂ bleed) to afford(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.1DMSO (29 g; 73% yield corrected for DMSO solvate).

¹H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.66 (d, J=7.9 Hz, 1H),7.54 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.9 Hz,1H), 6.56 (d, J=8.4 Hz, 1H), 4.99 (hept, J=6.3 Hz, 1H), 4.57 (d, J=8.8Hz, 1H), 4.02-3.85 (m, 1H), 3.27-3.09 (m, 2H), 2.96 (t, J=10.2 Hz, 1H),2.5 (s, 6H, DMSO), 2.35 (p, J=9.5 Hz, 1H), 2.02 (s, 3H), 1.95 (dd,J=12.1, 6.7 Hz, 1H), 1.72-1.59 (m, 6H), 1.58 (s, 3H), 1.55 (s, 3H), 1.43(d, J=40.1 Hz, 1H), 1.23 (d, J=6.3 Hz, 5H).

Example 12A: Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

A mixture of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(120 g of 86% w/w with IPAc [103.2 g(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione],0.21 mol, 1 equiv),3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole (42.6 g, 0.21mol, 1 equiv), K₂CO₃ (325 mesh, 63.4 g, 0.46 mol, 2.2 equiv), CuI (3.3g, 17.2 mmol, 0.083 equiv) and BuOAc (740 mL, 7.2 vol based on active(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione)was stirred at ambient temperature. DMF (300 mL, 2.9 vol) andN,N′-dimethylcyclohexane-1,2-diamine (14.6 g or 16.2 ml, 0.1 mol, 0.49equiv) were then added and the reactor contents purged with N₂. Themixture was then heated to 120° C. until the reaction is completed (˜4h).

The mixture was allowed to cool to ambient then 10% aq w/v oxalic acid(860 mL, 0.96 mol, 4.6 equiv) was added dropwise. The mixture wasstirred for at least 1 h then the solids were removed by filtration. Theremoved solids were washed with IPAc (2×120 mL). The organic layer wasisolated then washed with 8% aq w/v trisodium citrate (600 mL) then 1:1v/v water/brine (400 mL). The organic layer was filtered through a padof Celite. The filter pad was washed with IPAc (150 mL) and the filtrateconcentrated. 1-PrOH (800 mL of 7.8 vol) was added and the mixtureconcentrated. This step was repeated one more time then toluene (800 mL)was added and the mixture concentrated. This step is repeated one moretime to afford a thick slurry. The crude mixture was concentrated tovolume of 300 mL (2.9 vol) of toluene. (The mixture was seeded withCompound I Form A if the mixture is homogeneous). After stirring theslurry overnight, the solid was collected by filtration washing thesolid with toluene (2×100 mL, 0.97 vol). The solid is dried under vacuumto afford Compound I Form A as a white/off-white solid (107.0 g,83%,94.5% (AUC) HPLC purity).

Compound I Form A [22.2 g, 94.6% (AUC)] was suspended in toluene (440mL, 20 vol based on Compound I) and the mixture heated to reflux for atleast 2 h. The mixture was cooled over 8 h to ambient temperature thenstirred overnight. The solid was collected by filtration washing thesolid with toluene (40 mL, 1.8 vol). The solid was dried under vacuumwith a nitrogen bleed at 50° C. until the loss on drying is NMT 1.0% toafford Compound I Form A as a white/off-white solid (18.8 g, 84%, 96.8%(AUC) HPLC purity).

Compound I Form A [17.5 g, 97.0% (AUC)] was suspended in toluene (350mL, 20 vol) and the mixture heated to reflux. After holding at refluxfor at least 2 h, the mixture was cooled over 8 h to ambient temperaturethen stirred at ambient temperature overnight. The solid was collectedby filtration washing the solid with toluene (40 mL, 1.8 vol) then driedunder vacuum to afford Compound I Form A as a white/off-white solid(15.7 g, 89%,98.4% (AUC) HPLC purity).

¹H NMR (500 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83(d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d,J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H),4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d,J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H),1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65(dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

Example 12B: Alternative Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

A mixture of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(110 g, 182.441 mmol, 1.00 equiv, iPrOAc solvate),3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole (48.447 g,237.174 mmol, 1.3 equiv) and MEK (8 volumes) was heated to 40° C. thendegassed with N₂. tBuXphos Pd G3 (1.922 g, 2.372 mmol, 1.25 mol %) wasthen added to the mixture. A degassed solution of MTBD (67.034 g,428.737 mmol, 2.35 equiv) in MEK (2.00 vol) was then added to thereactor over 1 h while maintaining 40° C. The reaction was then stirredat 40° C. until completed (about 2 h) then cooled to 20° C. An aqueouswork-up was then performed with 1M HCl then the organic layer wasstirred with Silia Met S Thiol (66 g, 60% w/w relative to(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione)at 50° C. for 6 h. The mixture was cooled to 20° C. then filteredthrough Celite then concentrated under vacuum. The solvent was swappedby vacuum distillation to toluene (3 vol) then cooled to 20° C. andstirred for at least 3 h. The solid was isolated by filtration thendried under vacuum to afford Compound I Form A (92 g, 81% yield).

Example 13: Synthesis of benzyl(S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(45)

A stirred suspension of 6-bromo-2-fluoronicotinamide (40.0 g, 183 mmol),benzyl (S)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate.HCl (65.7 g,201 mmol; 1.1 equiv), and K₂CO₃ (30.3 g, 219 mmol) in acetonitrile (260mL) was warmed at 40° C. until the reaction was complete (˜20 h) thencooled to ambient temperature. Water (480 mL) was slowly added and theresulting solid was collected by filtration. The filter-cake was washedwith 2:1 water:CH₃CN (2×120 mL), then dried to afford benzyl(S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(86.8 g; 97%; 99.0% AUC) as an off-white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d, J=2.3 Hz, 1H), 7.40 (d, J=2.2 Hz,1H), 7.39-7.25 (m, 7H), 6.68 (d, J=7.7 Hz, 1H), 5.01 (s, 2H), 3.29-3.10(m, 2H), 3.00 (q, J=6.6 Hz, 2H), 2.19 (s, 1H), 1.90 (dd, J=11.8, 5.6 Hz,1H), 1.53 (s, 3H), 1.49 (s, 3H), 1.47-1.24 (m, 5H).

UPLC-MS: M+1=489/491 (conforms).

Example 14: Alternative Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

Step 1: Synthesis of benzyl(S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(51)

A suspension of benzyl(S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(85.0 g, 174 mmol),3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole (42.57 g, 208.4mmol, 1.2 equiv), K₂CO₃ (52.8 g, 382 mmol, 2.2 equiv), and(1R,2R)-N¹,N²-dimethylcyclohexane-1,2-diamine (19.8 g, 21.9 mL, 139mmol, 0.8 equiv) in DMF (425 mL) was purged with N₂ for 20 min. CuI (3.3g, 17 mmol, 0.1 equiv) was added and the mixture purged for anadditional 5 min, then heated at 90° C. until the reaction was completed(˜3.5 h). Next the reaction was cooled at ambient temperature. 2-MeTHF(850 mL) and 0.5 M NH₄OH (452 mL, 226 mmol) were added and the uppermostorganic phase was isolated then washed successively with 0.5 M NH₄OH(2×174 mL, 86.8 mmol), 0.5 M HCl (347 mL, 174 mmol), water (150mL)/brine (50 mL), and sat. NaHCO₃(50 mL). The solution was dried(Na₂SO₄) then concentrated to an oil. CH₃CN (255 mL) was added thenremoved under vacuum to afford a tan solid. The solid was slurried withCH₃CN (255 mL) at 40° C. for 20 min to give a suspension, which was thencooled to room temperature and stirred. The solid was isolated byfiltration then dried to afford benzyl(S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(70.4 g; 66%; 95.8% AUC) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J=2.7 Hz, 1H), 7.73 (s, 1H), 7.61(d, J=8.0 Hz, 1H), 7.42-7.20 (m, 7H), 6.84 (d, J=8.0 Hz, 1H), 6.05 (d,J=2.7 Hz, 1H), 5.01 (s, 2H), 4.20 (t, J=6.7 Hz, 2H), 3.32 (t, J=10.4 Hz,1H), 3.19 (t, J=8.8 Hz, 1H), 3.01 (q, J=6.5 Hz, 2H), 2.21 (s, 1H), 1.94(dd, J=11.9, 5.6 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.61 (s, 3H), 1.57 (s,3H), 1.53-1.23 (m, 6H), 0.90-0.77 (m, 4H), 0.67-0.60 (m, 2H), 0.53-0.46(m, 2H).

Step 2: Synthesis of benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(52)

A solution of benzyl(S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(68.0 g, 111 mmol) in 2-MeTHF (408 mL, 6 VolEq) was cooled to 0-5° C.,then 6-fluoropyridine-2-sulfonyl chloride (29.2 g of 92.9% w/w, 139mmol; 1.25 equiv) in 2-MeTHF (136 mL, 2 VolEq) was added. A 40% w/wheptane solution of lithium 2-methylbutan-2-olate (82.3, 255 mmol; 2.3equiv) was added slowly, maintaining the reaction temperature between0-5° C. The solution was stirred until the reaction was complete (30min), then EtOAc (408 mL, 6 VolEq) and a solution of NaHSO₄ (32.0 g, 266mmol, 2.4 equiv) in water (272 mL; 4 VolEq) were added. The organicphase was isolated then washed with water (272 mL; 4 VolEq), dried(Na₂SO₄), and concentrated to a brown semi-solid. MIBK (238 mL; 3.5VolEq) was added and the mixture was heated to 70° C., then seeded withcrystalline benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate,then allowed to cool to ambient temperature, then stirred for 2 h. Thesolid was collected by filtration then dried to afford benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(53.7 g, 63%; 97.5% AUC) as a white powder.

Additional product was obtained as a 2^(nd) crop after a SiO₂ plugfiltration followed by crystallization from i-PrOH/MIBK to afford benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(14.4 g; 17%; 92.5% AUC) as an off-white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (q, J=7.8 Hz, 1H), 8.13 (dd, J=7.4, 2.0Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d,J=4.2 Hz, 4H), 7.34-7.21 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8Hz, 1H), 5.05 (s, 2H), 4.22 (t, J=6.7 Hz, 2H), 3.01 (hept, J=6.7 Hz,2H), 2.46 (dd, J=10.4, 7.0 Hz, 1H), 2.13 (s, 1H), 1.89 (dd, J=11.8, 5.5Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.54 (s, 6H), 1.47 (t, J=6.5 Hz, 1H),1.34 (td, J=13.1, 12.6, 6.7 Hz, 3H), 1.17 (dt, J=16.1, 5.2 Hz, 1H), 0.97(dt, J=13.4, 8.8 Hz, 1H), 0.89-0.75 (m, 4H), 0.71-0.57 (m, 2H),0.56-0.41 (m, 2H).

¹⁹F NMR (376 MHz, DMSO-d₆) δ −65.73.

Step 3: Synthesis of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide((S)-53)

A suspension of benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(40.0 g, 51.8 mmol), ammonium formate (26.1 g, 415 mmol; 8 equiv), DABCO(116 mg, 1.03 mmol; 0.02 equiv), and 10% Pd on carbon (1.0 g, 0.94 mmol;0.02 equiv) in MeOH (240 mL; 6 VolEq) was stirred at ambient temperatureuntil the reaction was complete (˜70 min). The catalyst was removed byfiltration and the filtrate concentrated under vacuum to an oil. Themixture was slurried in MeTHF (200 mL) and EtOAc (200 mL) at 40° C. thenthe solid was removed by filtration. The filter-cake was rinsed with2-MeTHF (3×30 mL) then the combined filtrate and washings wereconcentrated under vacuum to afford(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(36.0 g; 102% of HCO₂H salt; 96.2% AUC) as a white, granular powderwhich was used without further purification.

¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (q, J=7.9 Hz,1H), 7.86 (dd, J=7.4, 2.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.24 (dd,J=8.3, 2.4 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 4.20(t, J=6.7 Hz, 2H), 3.15 (t, J=10.6 Hz, 1H), 3.06 (dd, J=10.9, 7.3 Hz,1H), 2.82 (hept, J=7.2, 6.3 Hz, 2H), 2.08 (s, 1H), 1.81 (q, J=6.5 Hz,2H), 1.55 (s, 5H), 1.51 (s, 3H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.27 (m,3H), 1.26-1.15 (m, 1H), 0.83 (d, J=5.5 Hz, 4H), 0.64 (dd, J=8.5, 4.2 Hz,2H), 0.50 (dd, J=8.5, 4.0 Hz, 2H).

Step 4: Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

A mixture of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide.HCO₂H(35.0 g, 51.2 mmol) and K₂CO₃ (21.2 g, 154 mmol; 3 equiv) in DMSO (350mL; 10 VolEq) was heated at 90° C. under a N₂ blanket for 6 h and thenallowed to cool to RT. The suspension was diluted with EtOAc (525 mL; 15VolEq) and water (280 mL; 8 VolEq). The phases were separated, and theaqueous phase extracted with EtOAc (210 mL). The combined organic phaseswere washed with a 20% w/v solution of citric acid (49.2 mL, 51.2 mmol)diluted in water (280 mL); the aqueous pH was 3-4. The organic phase wasthen washed with water (2×280 mL), dried (Na₂SO₄), and concentrated (40°C./30 torr) to afford crude Compound I (35.9 g; 114% theoretical yield;94.9% AUC) as a pale orange foam.

The crude product was dissolved in hot (105° C.) PhMe (210 mL; 6 VolEq);a yellow solution resulted at ˜40° C. The solution self-nucleated at−80° C. and gradual crystallization occurred. The reaction mixtureremained a suspension at 105° C. The suspension was cooled to 20° C. at10° C./h and allowed to stir overnight. The solid was collected byfiltration and the filter-cake was washed with PhMe (2×20 mL). The dampsolid was air-dried with suction and then vacuum-dried (50° C./300torr/N₂ bleed) to afford crystalline Compound I (25.3 g; 80%; 98.7% AUC)as a bright, white powder.

¹H NMR (500 MHz, DMSO-d₆) 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83(d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d,J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H),4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d,J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H),1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65(dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

UPLC-MS: [M+1]=618.5 (conforms).

Example 15: Alternative Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

Step 1: Synthesis of benzyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(47)

A reaction solution containing 6-fluoropyridine-2-sulfonyl chloride(459.5 mg, 2.349 mmol, 1.15 equiv), was diluted with 2-MeTHF (10 mL, 10VolEq), and benzyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(1.00 g, 2.043 mmol, 1.0 equiv) was added, then the mixture was cooledto 5° C. and lithium t-amoxide (40 w/w % solution in heptane, 1.20 g,5.108 mmol, 2.5 equiv) slowly added via syringe in order to maintain aninternal temperature of <7° C. Once the addition was complete, thereaction mixture was stirred and allowed to warm to room temperature andheld until reaction was complete (˜1 h). The reaction mixture was cooledto <10° C. and aq 1M HCl solution (8.172 mL, 8.172 mmol, 4.0 equiv) wasadded, to bring the mixture to pH=1. The phases were separated and theorganic phase was washed with water (5.000 mL, 5.0 VolEq), then washedwith brine (3.000 mL, 3.0 VolEq). The organic phase was transferred to aflask and concentrated to solid benzyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(1.38 g, 104.2% yield, not corrected for residual solvent).

¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 8.44-8.31 (m, 1H), 8.12 (d,J=7.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.41-7.22 (m, 5H), 6.78 (d, J=8.0Hz, 1H), 5.04 (s, 2H), 3.87-3.71 (m, 2H), 3.52 (q, 1H), 3.09-2.91 (m,2H), 2.11 (s, 1H), 2.01-1.68 (m, 1H), 1.46 (d, J=8.4 Hz, 6H), 1.39-1.24(m, 4H).

Step 2: Alternative Synthesis of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(48)

To a reaction vessel stirring at room temperature was added waterfollowed by sulfuric acid to prepare aqueous 9M H₂SO₄ (41.14 mL, 9.0 M,370.2 mmol). To the resulting solution was added benzyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)164yridine-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(8.0 g, 12.34 mmol, 1.0 equiv) and the resulting reaction mixture wasstirred at 30° C. until the reaction was deemed complete. The reactionmixture was cooled >10° C. and basified with aq NaOH (aq 4M solution,aprox 100 mL, 400 mmol) and diluted with 2-MeTHF (160.0 mL, 20.0 VolEq),stirred at 20-25° C., and separated. The aqueous phase was re-extractedwith 2-MeTHF (80.0 mL, 10.0 VolEq). The organic phases were combined andpartially concentrated (4-8 VolEq) allowing product to crystallize outof solution. The mixture was then filtered the solid rinsed with 2-MeTHF(16.0 mL, 2.0 VolEq), and the solid dried in vacuo to afford(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(2.96 g, 45%), as off-white crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (q, J=8.0 Hz, 1H), 7.83 (dd, J=7.3, 2.4Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.56 (d, J=7.6Hz, 1H), 3.86-3.79 (m, 0H), 3.77-3.68 (m, 0H), 3.55 (td, J=8.0, 6.4 Hz,0H), 3.03-2.87 (m, 2H), 1.97-1.89 (m, 0H), 1.86-1.77 (m, 1H), 1.46 (s,6H), 1.30 (ddt, J=12.9, 5.3, 3.8 Hz, 2H), 1.14-1.07 (m, 2H).

Step 3: Alternative Synthesis of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(40)

A mixture of(S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(2.80 g, 5.443 mmol, 1.0 equiv) in DMSO (28.00 mL, 10.0 VolEq) wasstirred and added MgCl₂ (518.2 mg, 5.443 mmol, 1.0 equiv) followed byaddition of K₂CO₃ (1.881 g, 13.61 mmol, 2.50 equiv, 325 mesh) andstirred at 80° C. until complete (20 h). The mixture was cooled to 10°C., diluted with EtOAc (42.00 mL, 15.0 VolEq) and acidified with aq 1MHCl (32.66 mL, 32.66 mmol, 6.0 equiv), The aqueous phase wasre-extracted with EtOAc (22.40 mL, 8.0 VolEq) and the organic phasescombined and washed with water (22.40 mL, 8.0 VolEq), then twice withbrine (8.400 mL, 3.0 VolEq). The solution was concentrated to afford2.59 g (yield=96%) of(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione,as amber foam.

¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 7.67-7.44 (m, 2H), 7.06 (d,J=7.2 Hz, 1H), 6.73 (dd, J=17.6, 8.2 Hz, 2H), 4.86 (p, J=6.3 Hz, 1H),3.87 (s, 1H), 3.09 (s, 1H), 2.94 (d, J=13.5 Hz, 1H), 2.61 (d, J=10.6 Hz,1H), 2.11 (s, 1H), 1.90-1.68 (m, 1H), 1.55 (s, 2H), 1.42 (s, 2H),1.36-1.23 (m, 1H), 1.17 (d, J=6.3 Hz, 6H).

Step 4: Alternative Synthesis of(14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(Compound I)

To a vessel was loaded DMF (17,500 mL, 7.0 VolEq), butyl acetate (17,500mL, 7.0 VolEq),(14S)-8-bromo-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione(2,500 g, 5,056.58 mmol, 1.00 equiv), and3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole (1,122.716 g,5,056.58 mmol, 1.00 equiv). The mixture was stirred at room temperature.then added K₂CO₃ (325 mesh, 1,537.514 g, 11,124.477 mol, 2.2 equiv), CuI(79.931 g, 419.696 mmol, 0.083 equiv) and trans-cyclohexane-1,2-diamine(238.794 g, 1,678.785 mmol, 0.332 equiv). The mixture was heated to 120°C. until complete. then the mixture was cooled >30° C. and aq oxalicacid (27.0 L of 0.8 M aqueous solution prepared by mixing 2,094.236 goxalic acid into 25,0000 mL water) was added to adjust the pH to >3. Theresulting mixture was diluted by addition of isopropyl acetate (7,500mL, 3.0 VolEq) and filtered through Celite washing with isopropylacetate (2,500 mL, 1.0 VolEq). The filtrate layers were allowed toseparate (slow). The organic phase was then washed with aqueous sodiumcitrate (8% solution, made from trisodium citrate 1,150.963 g, 4,459.904mmol, 5.0 equiv dissolved in 15.0 L, 6.0 VolEq water), the organic phasewas washed with brine (5.0 L, 2.0 VolEq of 10% w/w NaCl in watersolution), the organic phase was filtered through Celite, and the Celitecake rinsed with isopropyl acetate (2.5 L, 1.0 VolEq). The organic phasewas concentrated to a thick oil, that was diluted with toluene (50,000mL, 20.0 VolEq), transferred to a reactor (reactor jacket at 60° C.) andstirred, then heated to reflux, held at reflux for 2 h, then cooled to20° C. over 8 h, then filtered. The filter cake was washed with toluene(5.0 L, 2.0 VolEq) and dried in vacuo (50-55° C., vacuum) to affordCompound I (1,290 g, 41.296% yield) as a crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82(d, J=8.2 Hz, 1H), 7.58 (dd, J=8.5, 7.2 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H),6.97 (d, J=9.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H),6.08 (d, J=2.7 Hz, 1H), 4.21 (td, J=6.6, 1.4 Hz, 2H), 3.92 (d, J=12.0Hz, 1H), 3.15 (d, J=9.1 Hz, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.71 (t,J=10.5 Hz, 1H), 2.12 (s, 1H), 1.83 (tq, J=14.8, 8.1, 6.7 Hz, 4H),1.66-1.43 (m, 11H), 1.39-1.24 (m, 1H), 0.88-0.79 (m, 4H), 0.69-0.58 (m,2H), 0.54-0.44 (m, 2H).

Example 16: Synthesis of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

Step 1: Synthesis of 3-methylenetetrahydro-2H-pyran-2-one (5)

Step 1a: A 5 L 3-neck round bottom flask was fitted with a mechanicalstirrer, a heating mantle, an addition funnel, a J-Kem temperatureprobe/controller and a nitrogen inlet/outlet. The vessel was chargedunder a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w,1.498 mol) followed by heptane (1.5 L) which provided a grey suspension.Stirring was commenced and the internal temperature was recorded at 19°C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol)added via syringe, which resulted in gas evolution. The addition funnelwas charged with a clear pale yellow solution of tetrahydropyran-2-one(150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution wasadded dropwise over 1 h, which resulted in gas evolution and a gradualexotherm to 45° C. The resulting thick white suspension was then heatedto 65° C. for 2 h and then allowed to cool to room temperature. Themixture continued to stir at room temperature overnight (about 10 h).The reaction mixture was vacuum filtered through a glass frit Buchnerfunnel (Medium porosity) under a stream of nitrogen. The filter cake wasdisplaced and washed with heptane (2×250 ml) and pulled for a fewminutes. The slightly heptane wet cake was transferred to a glass trayand dried in a vacuum oven at 45° C. for 15 h to provide a white solid(205 g, 1.36 mol, 91% yield) as the desired product(E)-(2-oxotetrahydropyran-3-ylidene)methanolate.

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 3.90-3.83 (m, 2H), 2.09 (t,J=6.3 Hz, 2H), 1.57 (qd, J=6.4, 4.7 Hz, 2H).

Step 1b: A 5 L 3-neck round bottom flask was fitted with a mechanicalstirrer, a heating mantle, an addition funnel, a J-Kem temperatureprobe/controller and a nitrogen inlet/outlet. The vessel was chargedunder a nitrogen atmosphere with(E)-(2-oxotetrahydropyran-3-ylidene)methanolate-Na salt (205 g, 1.366mol) and tetrahydrofuran (1640 mL) which provided a white suspension.Stirring was commenced and the pot temperature was recorded at 19° C.The vessel was then charged with paraformaldehyde (136.6 g, 4.549 mol)added as a solid in one portion. The resulting suspension was heated to63° C. and the condition was maintained for 15 h. The resulting whitegelatinous mixture was concentrated under reduced pressure to removemost of the tetrahydrofuran. The remaining residue was partitioned withethyl acetate (1000 ml), saturated sodium chloride (500 ml) andsaturated sodium hydrogen carbonate (500 ml) in a separatory funnel. Theorganic phase was removed and the residual aqueous phase was extractedwith ethyl acetate (5×300 ml). The combined organic phases were driedover sodium sulfate (500 g) and then vacuum filtered through a glassfrit Buchner funnel with a 20 mm layer of Celite. The filter cake wasdisplacement washed with ethyl acetate (250 ml). The clear filtrate wasconcentrated under reduced pressure to provide a clear pale yellow oil(135 g), as the desired crude product. The material was purified byflash column chromatography eluting with a gradient of 100% hexane to60% ethyl acetate in hexane over 1 h collecting 450 ml fractions. Note:The product can be detected by TLC analysis on silica gel eluting with3:1 Hex/EtOAc and visualized under UV. The product fractions werecombined and concentrated under reduced pressure to provide a clearcolorless oil (132 g, 1.18 mol, 86% yield) as the desired product3-methylenetetrahydropyran-2-one.

¹H NMR (400 MHz, DMSO-d₆) δ 6.18 (q, J=1.9 Hz, 1H), 5.60 (q, J=1.9 Hz,1H), 4.40-4.26 (m, 2H), 2.61 (ddt, J=7.0, 6.3, 2.0 Hz, 2H), 1.90-1.75(m, 2H). The proton NMR indicates about 16 wt % residual ethyl acetate.The corrected yield would then be: (100-16=84) 0.84 (132)=110.9 g (72%yield).

Preparation of this compound in a one-pot procedure has been reported;see J. Org. Chem. 2016, 81, 11235-11249. Distillation of this compoundhas been reported at 52° C. and 0.2 Torr in Synthesis 1985, (1), 35-38.

Step 2: Synthesis of 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one((±)-4)

A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, acooling bath used as secondary containment, a J-Kem temperature probe,an addition funnel and a nitrogen inlet/outlet. The vessel was chargedunder a nitrogen atmosphere with 2-nitropropane (104.9 g, 1.177 mol).Stirring was commenced and the pot temperature was recorded at 19° C.The vessel was then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene(22.41 g, 147.2 mmol) added neat in one portion, which resulted in aclear light yellow solution. No exotherm was observed. The additionfunnel was charged with a solution of 3-methylenetetrahydropyran-2-one(110 g, 981.0 mmol) in acetonitrile (1100 mL), which was added dropwiseover 1 h resulting in a clear light yellow solution and a gradualexotherm to 24° C. The reaction mixture continued to stir at roomtemperature for 3.5 h and then concentrated under reduced pressure. Theremaining residue was dissolved in dichloromethane (1000 ml) andpartitioned with 500 ml of a 3:2 mixture of 1 M citric acidsolution/saturated sodium chloride solution. Note: The resulting organicphase is a clear pale blue solution and the aqueous phase is a slightlycloudy very pale blue solution. The organic phase was removed and theresidual aqueous was extracted with dichloromethane (300 ml). Thecombined organic phases were washed with saturated sodium chloridesolution (300 ml), dried over sodium sulfate (250 g) and then filteredthrough a glass frit Buchner funnel. The filtrate was concentrated underreduced pressure to a volume of about 200 ml. The clear pale bluedichloromethane solution was diluted with methyl tert-butyl ether (1500ml) and the cloudy solution was concentrated under reduced pressure to avolume of about 200 ml which provided a suspension. The mixture wasdiluted with methyl tert-butyl ether (1500 ml) and concentrated underreduced pressure to a volume of about 250 ml. The resulting suspensionwas allowed to stand at ambient temperature overnight (about 12 h). Thesolid was collected by vacuum filtration in a glass frit Buchner funneland the filter cake was displacement washed with cold methyl tert-butylether (2×150 ml) and then pulled for 30 min. The material was furtherdried in a vacuum oven at 45° C. for 5 h to provide the desired product3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (160 g, 0.795 mol, 81%yield), as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 4.34 (ddd, J=11.1, 9.3, 4.3 Hz, 1H), 4.20(dt, J=11.1, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 2.56 (dd, J=14.9, 5.2 Hz,1H), 2.01-1.89 (m, 2H), 1.89-1.67 (m, 2H), 1.55 (d, J=6.0 Hz, 6H), 1.44(dddd, J=12.8, 11.5, 8.1, 6.6 Hz, 1H). ESI-MS m/z calc. 201.10011, found202.0 [M+1].

Retention time: 0.97 min as an off white solid.

Step 3: Synthesis of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one((f)-3)

A solution of 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (122 g,606.3 mmol) in ethanol (2000 mL) purged with nitrogen then Raney Ni (40g of 50% w/w, 340 mmol) (washed twice with water and once with ethanol,by mixing and decantation) was added. The mixture was purged withnitrogen then hydrogen. The suspension was stirred vigorously and heatedat 60° C. for 20 h under hydrogen (1 atm). The reaction was cooled toroom temperature, then purged with nitrogen, filtered over celite andcarefully washed with ethanol to prevent the residual catalyst fromdrying out. The clear colorless filtrate was evaporated and the solidresidue (105 g) was suspended in MTBE (˜1.5 L) and concentrated atreflux to a thick suspension (˜200 mL MTBE). The solid was collected byfiltration and washed with dry ice-cold MTBE. This solid was dissolvedin DCM (˜300 mL) under warming and slowly diluted with MTBE (˜1 L) withseeding to give a colorless suspension. The colorless suspension wasconcentrated at 45° C. under reduced pressure to −500 mL and thesuspension was left stirring at room temperature overnight. Thecolorless suspension was filtered, washed with dry ice-cold MTBE anddried to give 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (94.1 g,88%)

¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H),1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H). ESI-MSm/z calc. 171.12593, found 172.0 [M+1]+.

Step 4: Synthesis of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

3-(3-Hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (1813 g) was separatedusing a Chiralpak® AZ column eluted with a isocratic mixture ofhexane:ethanol (85:15) at ambient temperature to afford(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (810 g) as acolorless solid after removal of the solvent.

98.6% enantiomeric excess (Chiralpak® AZ column, 210 nm); The(S)-enantiomer elutes at 13.1 min. The (R)-enantiomer elutes at 22.5min.

Example 17: Alternative Synthesis of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

Step 1: Synthesis of ethyl2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate ((f)-39)

A 500-mL jacketed reactor, equipped with a reflux condenser, nitrogenpurge, stirrer at 450 rpm, and jacket at 20° C., was loaded with3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (55.0 g, 273.3 mmol,1.0 equiv) and EtOH (440.0 mL, 8.0 vol), and stirred. The startingmaterial did not dissolve. To the reaction mixture was added HCl, 4MDioxane (13.67 mL of 4 M, 54.66 mmol, 0.20 equiv) causing a 2° C.temperature increase, followed by endotherm and drop in temperature to19° C. Starting material did not dissolve. The reaction progress wasfollowed by HPLC and deemed complete after 2 h (>98.0% conversion). Thereaction solution was neutralized with aqueous 20% KHCO₃ and theresulting mixture was then partially concentrated to remove bulk EtOH(75-85% of EtOH removed). The mixture was diluted with 2-MeTHF (550.0mL, 10.0 vol) and water (275.0 mL, 5.0 vol), then transferred back tothe 500 mL reactor, stirred, then stopped and layers allowed toseparate, and the aqueous layer drained. The organic layer was washedwith brine (165.0 mL, 3.0 vol). The organic layer was dried over Na₂SO₄,filtered through celite and cake washed with 2-MeTHF (110.0 mL, 2.0vol). The clear, light amber filtrate was concentrated to provide thedesired product ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitro-pentanoate(62.98 g, 93%) as light amber oil.

¹H NMR (400 MHz, DMSO-d₆) δ 4.43 (br s, 1H), 4.04 (q, J=7.1 Hz, 2H),3.35 (t, J=6.3 Hz, 2H), 2.38-2.24 (m, 2H), 2.07-1.96 (m, 1H), 1.50 (m,7H), 1.46-1.28 (m, 1H), 1.18 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of ethyl(S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (39)

A 500 ml jacketed reactor, equipped with reflux condenser and nitrogenpurge, stirrer at 450 rpm, jacket at 35° C. was loaded with pH 7.93Phosphate buffer, 0.8M (250.0 mL) and ethyl2-(3-hydroxypropyl)-4-methyl-4-nitro-pentanoate (5 g, 20.22 mmol, 1.0equiv) and stirred to produce a suspension. Enzyme Lipase fromRhizomucor miehei (125.0 mL, 25.0 vol, Palatase® 20,000 L) was added.The resulting reaction mixture was sampled and had a starting pH of7.63. Reaction allowed to run at 35° C. The reaction progress wasfollowed by chiral GC, and deemed complete after two days (>99.0% ofdesired ester remains). Once complete, the reaction was cooled to 20° C.and the product extracted into MTBE (250.0 mL, 50 vol), resulting in alarge emulsion in the organic layer, that was separated from the aqueouslayer. The aqueous layer was re-extracted with MTBE (125.0 mL, 25.0vol). The emulsified organic layers were combined and filtered throughCelite to break up the emulsion, returned to the rinsed reactor, and theaqueous phase was separated from the organic layer. The organic(product) layer was washed with 20% aq Na₂CO₃ (50.00 mL, 10.0 vol), 20%aq Na₂CO₃ (25.00 mL, 5.0 vol), 20% aq Na₂CO₃ (25.00 mL, 5.0 vol), andlastly with 20% aq Na₂CO₃ (25.00 mL, 5.0 vol). The organic layer wasthen washed with water (25.00 mL, 5.0 vol), then with 10% brine (25.00mL, 5.0 vol). The washed organic layer was concentrated in a rotovap(45° C., vacuum) to provide 2.01 g of ethyl(S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate as light amber oil,enriched to 99.7% of desired enantiomer.

Step 3: Synthesis of(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

Ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (5 g, 20.22mmol) in ethanol (250 mL) was cycled three times with vacuum/nitrogenand Raney Ni (2.374 g of 50% w/w, 20.22 mmol) (washed twice with waterand once with ethanol, by mixing and decantation) was added. The mixturewas cycled three times vacuum/nitrogen and then three timesvacuum/hydrogen. The suspension was stirred vigorously and heated at 60°C. under hydrogen (2 bar) until the reaction was completed.

The reaction was cooled to room temperature, cycled 3 times withvacuum/nitrogen, filtered over Celite and washed with ethanol (50 mL).The solvent was removed from the filtrate then MeCN (50 mL) was addedthen the solvent was removed to afford(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (2.88 g, 83%) asoff-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H),1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H).

ESI-MS m/z calc. 171.12593, found 172.0 [M+1]+.

Example 18: Synthesis of tert-butyl(S)-2,2-dimethyl-4-(3-((6-sulfamoylpyridin-2-yl)amino)propyl)pyrrolidine-1-carboxylate

Step 1: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2)

To a 50 L reactor, stirring at 150 rpm, equipped with a jacket set to40° C. and reflux condenser (10° C.) with nitrogen purge, was added2-MeTHF (10.00 L, 10 vol) followed by portion-wise addition of LAHpellets (332.5 g, 8.760 mol, 1.50 equiv). After pellet addition, theinternal temperature was recorded at 38° C. The stirrer speed was thenadjusted to 175 rpm, and the mixture was heated to 75° C. internaltemperature. To a 20 L RBF was added(S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840mol, 1.00 equiv) and 2-MeTHF (10.00 L, 10 vol). The resulting mixturewas stirred and heated in a water bath at 65° C. The resulting mixturewas added over the course of 2 h into the reactor containing the LAHmixture via an addition funnel, which was heated. The mixture wasstirred and then quenched using the Fieser method. Water was addeddrop-wise (400.0 mL, 1×LAH wt), at 3.5° C., jacket at −2° C., usingreactor temperature control, maintaining internal temperature control<30° C. Sodium hydroxide (aqueous, 15%; 400.0 mL, 1×LAH wt) was added,followed by portion-wise addition of water (400.0 mL, 1×LAH wt). Theresulting mixture was heated to 60° C. for at least 30 min, and thencooled to 25±5° C. Celite (200 grams, 20 wt %) was added, stirred, andthen packed a 12-inch diameter QVF filter with a half-inch layer ofCelite and filtered the mixture from the reactor. The reactor was rinsedwith 2-MeTHF (4.0 L, 4.0 vol) and the resulting mixture was filtered.The filtrate (clear, light amber) was concentrated in vacuo (50° C.bath, vacuum) to afford a clear oil (872 grams, 94.95% yield).

Step 2: Synthesis of tert-butyl(S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (42)

To a 50 L glass, jacketed reactor, with the jacket set to 20° C.,stirring at 175 rpm, and condenser set at 20° C., with N₂ purge, wasadded water (3.480 L, 4.0 vol) and potassium carbonate (1.914 kg, 13.85mol, 2.5 equiv). To the resulting mixture was then added a solution of(S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (870 g, 5.532 mol, 1.0equiv) in 2-MeTHF (3.480 L, 4.0 vol). 2-MeTHF (3.480 L, 4.0 vol) andBoc₂O (1.096 kg, 5.023 mol, 0.90 equiv) were combined in a glasscontainer. The reactor temperature was set to maintain 20° C. beforeaddition of mixture of 2-MeTHF and Boc₂O via addition funnel over thecourse of 35 min. The resulting mixture was stirred for 30 min.

To the resulting emulsion was added L-glutamic acid (203.5 g, 1.383 mol,0.25 equiv) and the emulsion was stirred overnight at room temp. Thestirrer was stopped and layers allowed to separate. Water (2.610 L, 3.0vol) was added, and the mixture stirred. The organic layer was isolated,and the aqueous layer was extracted with 2-MeTHF (2.610 L, 3.0 vol). Thecombined organic layers were washed with aqueous sodium bisulfate (0.5M, 1.740 L, 2.0 vol), aq layer pH acidic, then washed with aq 0.5MNaHSO₄ (870.0 mL, 1.0 vol). The organic layer was then washed with Aq0.5M K₂CO₃ (1.740 L, 2.0 vol) (pH 12 with pH strip), and aq 0.5M K₂CO₃(1.740 L, 2.0 vol). The organic layer was then washed with brine (870.0mL, 1.0 vol), then dried over Na₂SO₄, and filtered through Celite. Thefilter cake was rinsed with 2-MeTHF (870.0 mL, 1.0 vol). The filtratewas concentrated in vacuo to afford tert-butyl(S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1,336 g,94%) as a clear, viscous oil.

Step 3: Synthesis of tert-butyl(S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate

To a 50 L jacketed reactor, with jacket set to 20° C., stirring at 175rpm, a reflux condenser (10° C.), and a nitrogen purge was addedtert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate(1,330 g, 5.168 mol, 1.0 equiv), DCM (7.980 L, 6.0 vol) and4-nitrobenzenesulfonyl chloride (1.753 kg, 7.752 mol, 1.50 equiv). Theresulting mixture was stirred with a reactor internal temperature of 5°C. Triethylamine (1.046 kg, 10.34 mol, 2.0 equiv) was added via additionfunnel at a rate to maintain a reaction temperature of less than 15° C.

The resulting mixture was stirred for approximately 30 min before water(3.990 L, 3.0 vol) and saturated aqueous sodium bicarbonate (2.660 L,2.0 vol) were added. The resulting mixture was stirred and warmed toroom temperature. Addition exotherm went from 5° C. to 12° C. at thisscale, jacket then set to 20° C. Stirring was then stopped, the organicwas isolated and washed with saturated aqueous sodium bicarbonate (3.990L, 3.0 vol). The amber organic solution was dried over sodium sulfate,and filtered through Celite. The filter cake was washed with DCM (1.330L, 1.0 vol). The filtrate was partially concentrated in vacuo, and thenIPA (5.320 L, 4.0 vol) was added. Partially concentrated in vacuo andadded seed material (tert-butyl(S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate,250 mg), returned flask to rotovap, stirred at room temp overnight, thenadded ice-water bath, continued stirring, cooling for 1-2 h. The mixturewas filtered through a QVF filter (12-inch diameter). The filter cakewas washed with cold IPA (1.330 L, 1.0 vol), and the filter cake wasscooped into a rotovap flask and dried in vacuo (50° C., rotovap,vacuum). The solid was dried to 2,091 grams (91.43% yield) as beigecolored fine solid.

Step 4: Synthesis of tert-butyl(S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (44)

Step 4a: To a 50 L jacketed reactor with a jacket set to 20° C.,stirring at 175 rpm, and a reflux condenser (10° C.) with nitrogen purgewas added tert-butyl(S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate(2090 g, 4.723 mol, 1.00 equiv) and NMP (10.45 L, 5.0 vol). The systemwas set to maintain an internal temperature of 20° C. while stirring.Sodium azide (307.0 g, 4.723 mol, 1.00 equiv) was added in two portionsinto the reactor and rinsed in with NMP (2.090 L, 1.0 vol). Theresulting mixture was stirred for 1 h before diluting with 2-MeTHF(25.08 L). The organic layer was isolated, washed with 1:1 water,saturated NaHCO₃solution (16.72 L, 8.0 vol). Additional water was added(4.180 L, 2.0 vol), stirred, and then allowed to separate. The aqueouslayer was extracted with 2-MeTHF (6.270 L, 3.0 vol). The organic layerswere combined and washed with 2:1 water/sodium bicarbonate (6.270 L, 3.0vol total, 2 vol water:1 vol bicarb), and then washed with 2:1water/brine (6.270 L, 3.0 vol), 1:1 water/brine (4.180 L, 2.0 vol), andwith brine (4.180 L, 2.0 vol). The organic layer was dried over sodiumsulfate then filtered through Celite. The filter cake was washed with2-MeTHF (2.090 L, 1.0 vol), and the filtrate was partially concentratedin the rotovap to 5+/−1 volumes. Concentrated to 3.02 kg as clear ambersolution. Estimate 75% yield that was used without further purification.

Step 4b: To a Buchi 1 L pressure system with a jacket at 20° C., purgingwith nitrogen was added tert-butyl(4S)-4-(3-azidopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (200 g,708.3 mmol) solution in 2-MeTHF (˜700 mL), followed by addition ofplatinum oxide (2.0 g, 8.85 mmol, 1.0 wt %), and rinsed in with 2-MeTHF(50.00 mL, 0.25 vol). The resulting mixture was stirred at 400 rpm andthe reaction chamber was degassed with three cycles of N₂/vacuum,followed with three cycles of H₂/vacuum. The H₂ pressure was set to 2.0bar and system set for automatic H₂ feed, maintaining 2.0 bar, stirringincreased to 900 rpm at 21.1° C. Then, with the jacket set to 20° C.,the headspace was evacuated by cycling nitrogen/vacuum times. Thereaction mixture was filtered through Celite. The filter cake was rinsedwith 2-MeTHF (100.0 mL, 0.5 vol), and the filtrate transferred to astirred vessel and diluted with 2-MeTHF (2000.0 mL, 10.0 vol), followedby addition of cold aqueous 1N HCl (1.062 L of 1 M, 1.062 mol, 5.0 vol)while stirring. The stirring was stopped, the pH was measured withindicating strips, and the layers separated. The organic layer wasextracted with cold aqueous 1 N HCl (354.1 mL of 1 M, 354.2 mmol, 0.5equiv). The aqueous layers were combined in the reactor and stirred atroom temp. 2-MeTHF (1.600 L, 8.0 vol) was added and the mixture wasbasified by adding aqueous (4 M) NaOH (approximately 354.2 mL of 4 M,1.417 mol) as needed. The layers were separated, then drained into cleancontainer. The aqueous layer was isolated and extracted with 2-MeTHF(400.0 mL, 2.0 vol). The organic layers were combined and added to thereactor, then washed with brine (600.0 mL, 3.0 vol) then dried oversodium sulfate then filtered through celite. The filter cake was rinsedwith 2-MeTHF (400.0 mL, 2.0 vol). The filtrate was concentrated in vacuo(50° C., vacuum) to afford an oil. The material was used without furtherpurification.

Step 4c: The crude amine oil (990 grams, 3.87 mol) was diluted with2-MeTHF (25.0 L, 25 vol) transferred into a 50 L reactor, and stirred at25° C. Measured the required amount of oxalic acid (208.9 grams, 425.0mmol, 0.60 equiv) and dispensed into a glass carboy, then added 2-MeTHF(5.0 L, 5.0 vol) and stirred to dissolve the acid. Began slow additionof the oxalic acid solution to the amine solution. Note that salts startforming on addition and may require slow addition to prevent largechunks of solid from forming. Salts appeared to form a gel that slowlychanged. The mixture was stirred at room temp overnight. Appearance ofthe solid changed from a gel to a mixture containing fine solids. Themixture was filtered (slow filtration), cake then washed with 2-MeTHF(4.00 L, 4.0 vol) and pulled dry in the filter. The cake was scooped outof the filter and dried in vacuo (50° C., vacuum, rotovap). Obtained1,057 grams of tert-butyl(S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate hemi-oxalatesalt, as an off-white solid. The crude amine oil (990 grams, 3.87 mol)was diluted with 2-MeTHF (25.0 L, 25 vol) transferred into a 50 Lreactor, and stirred at 25° C. Oxalic acid (208.9 grams, 425.0 mmol,0.60 equiv) was measured and dispensed into a glass carboy, thendissolved in 2-MeTHF (5.0 L, 5.0 vol) with stirring to dissolve theacid. Slow addition of the oxalic acid solution to the amine solutionwas carried out. Note that salts start forming on addition and mayrequire slow addition to prevent large chunks of solid from forming.Salts appeared to form a gel that slowly changed. The mixture wasstirred at room temp overnight. The appearance of the solid changed froma gel to a mixture containing fine solids. The mixture was filtered(slow filtration), cake then washed with 2-MeTHF (4.00 L, 4.0 vol) andpulled dry in the filter. The cake was scooped out of the filter anddried in vacuo (50° C., vacuum, rotovap). Obtained 1,057 grams oftert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylatehemi-oxalate salt as an off-white solid.

Example 19: Synthesis of2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinicacid

Step 1: Synthesis of ethyl2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate

A suspension of 3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazole(40.0 g, 196 mmol), ethyl 2,6-dichloronicotinate (43.1 g, 196 mmol), andK₂CO₃ (35.2 g, 255 mmol) in DMF (240 mL) was stirred at RT. Dissolutionresulted in an endotherm from 22 to 16° C. In one portion, DABCO (3.3 g,29 mmol) was added. The addition was mildly exothermic and raised thereaction temperature from 17 to 23° C. over 20 min. The reactiontemperature was maintained at 20-30° C. After ˜20 h, HPLC analysisshowed the reaction was completed (no ethyl 2,6-dichloronicotinateremained; 90% AUC). The mixture was diluted with drop-wise addition ofwater (400 mL)-white solid formed and the temperature gradually rosefrom 22 to 32° C. The mixture was re-cooled to maintain the temperatureat 15-25° C. After an unsuccessful filtration (solid blinded the filter)the suspension was diluted with EtOAc (480 mL) and the phases wereseparated. The organic phase was washed with water (200 mL)/brine (50mL) (2×); the organic phase was dried (Na₂SO₄) and concentrated (40°C./30 torr) to afford crude ethyl2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate(73.1 g; 96%) as an amber oil which became crystalline.

The crude solid was dissolved in warm (80° C.) i-PrOH (200 mL) andallowed to cool to RT over 2 h. The solution was seeded at 38-40° C. fora slow nucleation/crystallization event. At 35-34° C. muchcrystallization was observed. The suspension was allowed to stir at RTovernight.

The resultant suspension was very thick (oatmeal consistency). The solidwas collected by filtration (sintered-glass/paper); the filter-cake waswashed with i-PrOH (50 mL), air-dried with suction and then vacuum-dried(55° C./300 torr/N₂ bleed) to afford ethyl2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate(60.2 g; 79%; 98.6% AUC) as a white powder. The filtrate was cooled to3° C. and a 2^(nd) crop was collected (5.8 g; 8%) as a white powder ofacceptable purity (98% AUC). Total Yield: 60.2+5.8=66.0 g (87%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.45-8.36 (m, 2H), 7.73 (d, J=8.3 Hz, 1H),6.19 (d, J=2.8 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.25 (t, J=6.7 Hz, 2H),1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.6 Hz, 1H), 1.34 (t, J=7.1 Hz, 4H),0.89-0.77 (m, 1H), 0.83 (s, 4H), 0.71-0.60 (m, 3H), 0.54-0.44 (m, 2H).

Step 2: Synthesis of2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinicacid

A solution of ethyl2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate(62.0 g, 160 mmol) in THF (248 mL) and EtOH (186 mL) was stirred atambient temperature (13° C.). A 2 M aqueous solution of NaOH(approximately 96 mL; 192 mmol) was added in one portion; an exothermfrom 13 to 20° C. was observed. After 1 h, UPLC-MS analysis showedreaction completion. The reaction solution was concentrated (40° C./50torr) to remove most of the organic solvent. The concentrate was dilutedwith water (248 mL) and 2-MeTHF (750 mL) and then 2 M HCl (100 mL, 200mmol) was added while maintaining the internal temperature below 20° C.The phases were separated and the organic phase was washed with water(2×200-mL); dried (Na₂SO₄), and concentrated to afford crude2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinicacid (62.4 g (109% of theory) as a white powder. The product containssome residual solvent(s).

The crude product was recrystallized from warm (106° C.) PhMe (5 VolEq),seeded at −95° C. and cooled to RT over 2 h and then further to 10° C.The solid was collected by filtration, washed with cold PhMe (1 VolEq),and the filter-cake was dried with suction and then in a vacuum oven(40° C./100 torr) to afford2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinicacid (88% yield) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (s, 1H), 8.44-8.36 (m, 2H), 7.72 (d,J=8.4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q,J=6.7 Hz, 2H), 1.47 (t, J=6.5 Hz, 1H), 0.89-0.77 (m, 2H), 0.83 (s, 2H),0.71-0.60 (m, 2H), 0.50 (ddd, J=8.2, 4.5, 2.2 Hz, 2H).

Example 20: Synthesis of(14R)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

Step 1: Synthesis of tert-butyl(R)-4-(3-(((benzyloxy)carbonyl)amino)propyl)-2,2-dimethylpyrrolidine-1-carboxylate

A biphasic mixture of tert-butyl(4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (22.0 g,85.8 mmol) in PhMe (132 mL) and NaOH (86 mL of 2 M, 172 mmol) was cooledat 0-10° C., then a solution of Cbz-Cl (22.0 g, 18.4 mL, 129 mmol) inPhMe (44 mL) was added over 15 min while maintaining the reactiontemperature below 10° C. Once the reaction was complete, the biphasicmixture was warmed to room temperature and the phases were separated.The aqueous phase was extracted with PhMe (44.00 mL) then the combinedorganic phases were washed with water (88 mL), dried (Na₂SO₄), andconcentrated to afford tert-butyl(4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(36.1 g; 108%) as a colorless oil.

Step 2: Synthesis of benzyl(R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

A solution of tert-butyl(4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(30.0 g, 76.8 mmol) in DCM (60 mL) was treated with HCl (96 mL of 4 M,384 mmol) in dioxane and stirred at room temperature until the reactionwas complete, then the solvents were removed under vacuum. Theconcentrate was partitioned between water (180 mL) and MTBE (120 mL) andthe phases were separated. The aqueous phase was washed with MTBE (120mL). The aqueous phase was diluted with MTBE (180 mL) and basified withNaOH (46 mL of 2 M, 92 mmol) (pH ˜14). The phases were separated and theaqueous phase was extracted with MTBE (120 mL). The combined organicphases were dried (Na₂SO₄) and concentrated (40° C./20 torr) to affordbenzyl N-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propyl]carbamate (15.2 g,68%) as a colorless liquid.

UPLC-MS analysis: tR=0.99 min/M+1=291 (conforms to structure).

¹H NMR (400 MHz, Chloroform-d) δ 7.43-7.23 (m, 5H), 5.09 (s, 2H), 4.79(s, 1H), 3.26-3.05 (m, 3H), 2.55 (dd, J=11.0, 8.0 Hz, 1H), 2.13 (dq,J=15.5, 7.8 Hz, 1H), 1.79 (dd, J=12.5, 8.0 Hz, 2H), 1.48 (q, J=7.3 Hz,2H), 1.37 (ddd, J=9.8, 7.2, 3.3 Hz, 2H), 1.18 (s, 3H), 1.12 (s, 4H).

Step 3: Synthesis of2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinicacid

To a solution of tert-butyl2-chloro-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate(10.0 g, 24.0 mmol) in DCM (100 mL) was added trifluoroacetic acid (26mL, 338 mmol). The reaction stirred under nitrogen gas at roomtemperature for 16 h. The reaction mixture was concentrated to afford awhite solid. To the white solid was added MTBE and the mixture wasconcentrated three times to give2-chloro-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (9.00 g, 96%). The crude NMR showed MTBE and some baselineimpurities.

¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (s, 1H), 8.50-8.32 (m, 2H), 7.72 (d,J=8.4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q,J=6.7 Hz, 2H), 1.47 (t, J=6.5 Hz, 1H), 0.88-0.78 (m, 4H), 0.68-0.61 (m,2H), 0.50 (ddd, J=8.2, 4.5, 2.2 Hz, 2H).

Step 4: Synthesis of2-chloro-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-H-pyrazol-1-yl)nicotinamide

A suspension of2-chloro-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (7.5 g, 20.8 mmol) in 2-MeTHF (45 mL) and DMF (152 mg, 161 μL, 2.1mmol) was stirred at room temperature then SOCl₂ (3.35 g, 2.05 mL, 28.1mmol) was added and heated at 40° C. Once the reaction was completed,the reaction was added to a separate flask containing a cooled solutionof NH₄OH (approximately 28 mL of 14.8 M, 417 mmol) in water (26 mL)while maintaining the internal temperature below 15° C. Once thereaction was completed (20 min) the mixture was diluted with MTBE (120mL) and water (60 mL) then EtOAc (180 mL). The phases were separatedthen the organic phase was dried (Na₂SO₄) and concentrated to afford abeige powder. The powder was stirred with MTBE (50 mL; 7 VolEq) andwarmed to form a slurry then cooled to room temperature. The solid wascollected by filtration then rinsed with MTBE (2×5-mL) and dried toafford2-chloro-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxamide(6.70 g; 90%) as an off-white powder.

HPLC analysis: 98.6% AUC (272 nm)

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=2.8 Hz, 1H), 8.04 (d, J=8.3 Hz,1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 6.13 (d, J=3.0Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.5Hz, 1H), 0.90-0.76 (m, 4H), 0.69-0.58 (m, 2H), 0.56-0.45 (m, 2H).

Step 5: Synthesis of benzyl(R)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

A suspension of2-chloro-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxamide(5.0 g, 13.9 mmol), benzylN-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propyl]carbamate (4.86 g, 16.7mmol), K₂CO₃ (approximately 5.8 g, 42 mmol), and ZnCl₂ (approximately1.9 g, 14 mmol) in n-BuOAc (40 mL) was heated at 120° C. until thereaction was complete (˜2.5 days).

The suspension was diluted with EtOAc (60 mL) and acidified with HCl(approximately 42 mL of 2 M, 84 mmol); C₀₂ degassing; pH ˜1. The phaseswere separated and the aqueous phase was extracted with EtOAc (60 mL);combined organic phases and washed with water (60 mL), dried (Na₂SO4),and concentrated to afford 14.0 g (164%) of a dark amber liquid(residual n-BuOAc remained).

Diluted with DCM and purified by flash column chromatography elutingwith EtOAc/hexanes. The fractions containing the desired product werecombined and concentrated to afford benzylN-[3-[(3R)-1-[3-carbamoyl-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate(3.05 g; 36%) as a yellow foam.

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J=2.7 Hz, 1H), 7.73 (s, 1H), 7.61(d, J=8.0 Hz, 1H), 7.42-7.20 (m, 7H), 6.84 (d, J=8.0 Hz, 1H), 6.05 (d,J=2.7 Hz, 1H), 5.01 (s, 2H), 4.20 (t, J=6.7 Hz, 2H), 3.32 (t, J=10.4 Hz,1H), 3.19 (t, J=8.8 Hz, 1H), 3.01 (q, J=6.5 Hz, 2H), 2.21 (s, 1H), 1.94(dd, J=11.9, 5.6 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.61 (s, 3H), 1.57 (s,3H), 1.53-1.23 (m, 6H), 0.90-0.77 (m, 4H), 0.67-0.60 (m, 2H), 0.53-0.46(m, 2H).

Step 6: Synthesis of benzyl(R)-(3-(1-(6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

A solution of benzylN-[3-[(3R)-1-[3-carbamoyl-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate(2.50 g, 4.08 mmol) in 2-MeTHF (15 mL) was cooled at 0-5° C. then asolution of 6-fluoropyridine-2-sulfonyl chloride (approximately 1.19 g,6.12 mmol) in 2-MeTHF (5 mL) was added, followed by lithium2-methylbutan-2-olate (3.3 mL of 40% w/w, 10.2 mmol) over 15 min whilemaintaining the reaction temperature below 5° C. Analysis showed 10-15%of unreacted starting material, so an additional portion of6-fluoropyridine-2-sulfonyl chloride (0.20 g, 1.0 mmol), followed bylithium 2-methylbutan-2-olate (330 μL of 40% w/w, 1.0 mmol), were added.The mixture was stirred until the reaction was complete (˜20 min) thenpartitioned between EtOAc (20 mL) and HCl (12 mL of 1 M, 12 mmol). Thephases were separated and the organic phase was washed with water (10mL), then dried (Na₂SO₄) and concentrated to afford a brown taffy/foam.Purification by normal phase column chromatography (gradientEtOAc/hexanes) followed by reversed-phase column chromatography(gradient CH₃CN/H₂O) afforded benzylN-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate(1.10 g; 35%; 97+% AUC) as a white powder.

A less pure fraction (0.80 g; 84% AUC) was dissolved in warm EtOH (˜10mL), stirred, and allowed to cool to RT. After ˜10 min crystallizationoccurred. The suspension was stirred for ˜1 h and the solids werecollected by filtration (fritted syringe). The filter-cake was rinsedwith EtOH (3 mL) and the solid air-dried/vacuum dried (55° C.) to affordadditional benzylN-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate(0.61 g; 76% recovery) of a free-flowing, white powder.

HPLC analysis: 95.2% AUC (272 nm).

Total yield=1.10 g+0.61 g=1.71 g (54%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (q, J=7.8 Hz, 1H), 8.13 (dd, J=7.4, 2.0Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d,J=4.2 Hz, 4H), 7.34-7.21 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8Hz, 1H), 5.05 (s, 2H), 4.22 (t, J=6.7 Hz, 2H), 3.01 (hept, J=6.7 Hz,2H), 2.46 (dd, J=10.4, 7.0 Hz, 1H), 2.13 (s, 1H), 1.89 (dd, J=11.8, 5.5Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.54 (s, 6H), 1.47 (t, J=6.5 Hz, 1H),1.34 (td, J=13.1, 12.6, 6.7 Hz, 3H), 1.17 (dt, J=16.1, 5.2 Hz, 1H), 0.97(dt, J=13.4, 8.8 Hz, 1H), 0.89-0.75 (m, 4H), 0.71-0.57 (m, 2H),0.56-0.41 (m, 2H).

¹⁹FNMR (376 MHz, DMSO) δ −65.73.

Step 7: Synthesis of(R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide((R)-53)

A mixture of benzylN-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate(1.00 g, 1.30 mmol) and Pd on carbon (69 mg of 10% w/w) in MeOH (8 mL)was stirred under an atmosphere of H₂ (1 bar) at −40° C. until thereaction was completed (2.5 h). The catalyst was removed the catalyst byfiltration and the filtrate was concentrated to afford crude as a whitetaffy/solid. Purification by reversed-phase flash column (gradientCH₃CN/H₂O) followed by slurrying in MTBE (10 mL) afforded2-[(4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-N-[(6-fluoro-2-pyridyl)sulfonyl]pyridine-3-carboxamide(190 mg; 23%; 95.0% AUC) as a white powder.

¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (q, J=7.9 Hz,1H), 7.86 (dd, J=7.4, 2.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.24 (dd,J=8.3, 2.4 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 4.20(t, J=6.7 Hz, 2H), 3.15 (t, J=10.6 Hz, 1H), 3.06 (dd, J=10.9, 7.3 Hz,1H), 2.82 (hept, J=7.2, 6.3 Hz, 2H), 2.08 (s, 1H), 1.81 (q, J=6.5 Hz,2H), 1.55 (s, 5H), 1.51 (s, 3H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.27 (m,3H), 1.26-1.15 (m, 1H), 0.83 (d, J=5.5 Hz, 4H), 0.64 (dd, J=8.5, 4.2 Hz,2H), 0.50 (dd, J=8.5, 4.0 Hz, 2H).

Step 8: Synthesis of(14R)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

A suspension of2-[(4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-(2-dispiro[2.0.2⁴.1³]heptan-7-ylethoxy)pyrazol-1-yl]-N-[(6-fluoro-2-pyridyl)sulfonyl]pyridine-3-carboxamide(300 mg, 0.4704 mmol), K₂CO₃ (162.5 mg, 1.176 mmol), and MgCl₂ (44.79mg, 0.4704 mmol) in DMSO (2.400 mL) was heated at 80° C. for ˜6 h untilthe starting material was consumed. The suspension was partitionedbetween EtOAc (12 mL) and 0.5 M HCl (4.7 mL, 2.35 mmol). The phases wereseparated and the aqueous phase extracted with EtOAc (6 mL). Thecombined organic phases were washed with water (3×2-mL), dried (Na₂SO₄),and concentrated to afford(14R)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(262 mg; 90%) as an amber solid.

HPLC analysis showed 94.8% AUC with a trace (0.2%) of unreacted startingmaterial.

UPLC-MS analysis: M+1=618 (conforms to structure).

¹H NMR (500 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83(d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d,J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H),4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d,J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H),1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65(dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

Example 21: Synthesis of tert-butyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

A method for preparing tert-butyl(S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamateis shown in the above scheme. In some embodiments, N and O may have oneor more protecting groups selected from a range of protecting groupsdisclosed herein.

Example 22: Synthesis of(S)-6-bromo-2-(4-(3-(bis-Boc-amino)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

A method for preparing(S)-6-bromo-2-(4-(3-(bis-Boc-amino)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamideis shown in the above scheme. In some embodiments, N and O may have oneor more protecting groups selected from a range of protecting groupsdisclosed herein.

Example 23: Synthesis of benzyl(S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate(45)

An alternative method for preparing compound 45 is shown in the abovescheme. In some embodiments, N and O may have one or more protectinggroups selected from a range of protecting groups disclosed herein.

Example 24: Synthesis of(13S)-26-chloro-15,15-dimethyl-5-thia-4,7-diaza-2(2,3),6(2,6)-dipyridina-1(1,3)-pyrrolidinacyclodecaphan-3-one5,5-dioxide (41)

A method for preparing compound 41 is shown in the above scheme. In someembodiments, N and O may have one or more protecting groups selectedfrom a range of protecting groups disclosed herein.

Example 25: Synthesis of(R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-chloro-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

A method for preparing(R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-chloro-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamideis shown in the above scheme. In some embodiments, N and O may have oneor more protecting groups selected from a range of protecting groupsdisclosed herein.

Example 26: Diester enzymatic resolution of diethyl2-(2-methyl-2-nitropropyl)pentanedioate

A method for the chiral resolution of diethyl2-(2-methyl-2-nitropropyl)pentanedioate is shown in the above scheme. Insome embodiments, O may have one or more protecting groups selected froma range of protecting groups disclosed herein.

Example 27: Dinitrile enzymatic resolution of2-(2-methyl-2-nitropropyl)pentanedinitrile

A method for the chiral resolution of2-(2-methyl-2-nitropropyl)pentanedinitrile is shown in the above scheme.

Example 28: Ester Enzymatic Resolution of Ethyl2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoate (35)

A method for the chiral resolution of compound 35 is shown in the abovescheme. In some embodiments, N and O may have one or more protectinggroups selected from a range of protecting groups disclosed herein.

Example 29: Ester enzymatic resolution of ethyl2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-methyl-4-nitropentanoate

A method for the chiral resolution of ethyl2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-methyl-4-nitropentanoate shownin the above scheme. In some embodiments, N and O may have one or moreprotecting groups selected from a range of protecting groups disclosedherein.

Example 30: Enantioselective ring opening of ethyl4-cyano-6,6-dimethyl-2-oxotetrahydro-2H-pyran-3-carboxylate

A method for the chiral resolution of ethyl4-cyano-6,6-dimethyl-2-oxotetrahydro-2H-pyran-3-carboxylate is shown inthe above scheme. In some embodiments, O may have one or more protectinggroups selected from a range of protecting groups disclosed herein.

Example 31: Synthesis of 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol((f)-42)

A method for the chiral resolution of diethyl2-(2-methyl-2-nitropropyl)pentanedioate is shown in the above scheme. Insome embodiments, N and O may have one or more protecting groupsselected from a range of protecting groups disclosed herein.

Example 32: Synthesis of2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione

A method for the chiral resolution of2-(2-methyl-2-nitropropyl)pentanedinitrile is shown in the above scheme.In some embodiments, N and O may have one or more protecting groupsselected from a range of protecting groups disclosed herein.

Example 33: Synthesis of tert-butyl(3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate

A method for preparing tert-butyl(3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate is shown inthe above scheme. In some embodiments, N and O may have one or moreprotecting groups selected from a range of protecting groups disclosedherein.

Example 34: Synthesis of tert-butyl(S)-(3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl)carbamate

A method for preparing tert-butyl(S)-(3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl)carbamate is shown inthe above scheme. In some embodiments, N and O may have one or moreprotecting groups selected from a range of protecting groups disclosedherein.

Example 35: Synthesis of tert-butyl(S)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (31)

A method for preparing compound 31 is shown in the above scheme. In someembodiments, N and O may have one or more protecting groups selectedfrom a range of protecting groups disclosed herein.

Example 36: Synthesis of tert-butyl(3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate

A method for preparing tert-butyl(3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate is shown inthe above scheme. In some embodiments, N and O may have one or moreprotecting groups selected from a range of protecting groups disclosedherein.

Example 37: Synthesis of 3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propylbenzoate

A method for preparing 3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propylbenzoate is shown in the above scheme. In some embodiments, N and O mayhave one or more protecting groups selected from a range of protectinggroups disclosed herein.

Example 38: Synthesis of tert-butyl4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate

A method for preparing tert-butyl4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylateis shown in the above scheme. In some embodiments, N and O may have oneor more protecting groups selected from a range of protecting groupsdisclosed herein.

Example 39: Synthesis of1-benzyl-3-(3-(benzyloxy)propyl)-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one

A method for preparing1-benzyl-3-(3-(benzyloxy)propyl)-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-oneis shown in the above scheme. In some embodiments, N and O may have oneor more protecting groups selected from a range of protecting groupsdisclosed herein.

Example 40: Synthesis of Pyrroline

A method for preparing the pyrroline is shown in the above scheme. Insome embodiments, N and O may have one or more protecting groupsselected from a range of protecting groups disclosed herein.

Example 41: Synthesis of 7,7-dibromodispiro[2.0.2⁴.1³]heptane (54)

Compound 18 was prepared by reacting compound 19 with Ti(Oi-Pr)₄ andEtMgBr in the presence of MTBE at 20° C. to 25° C. for 14 h. Compound 17was prepared by reacting compound 18 with PPh₃, Br₂, and pyridine in thepresence of DCM at −30° C. to 15° C. for 14 h, then distilling thereaction mixture. Compound 16 was prepared by reacting compound 17 withKOt-Bu in the presence of DMSO at 20° C. to 25° C. for 16 h. Compound 54was prepared by reacting compound 16 with KOt-Bu and CHBr₃ in thepresence of heptane at 0° C. to rt for 17-72 h.

Example 42: Alternative Synthesis of2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethan-1-ol (8)

Compound 55 was prepared by reacting compound 54 with vinylmagnesiumbromide and copper(I) iodide in the presence of THF at −40° C. to −10°C. for 4 h. Compound 55 was then reacted with borane-THF, hydrogenperoxide, and sodium hydroxide at 0° C. to provide compound 8.

Example 43: Alternative Synthesis of2-(dispiro[2.0.2⁴.1³]heptan-7-yl)ethan-1-ol (8)

Compound 56 can be prepared by first reacting compound 54 withtert-butylmagnesium chloride and iron(III) acetylacetonate at −10° C.Compound 56 can then be treated in a first step with magnesium metal andiodine in the presence of THF at 50° C., and in a second step withethylene oxide and Li₂CuCl in the presence of THF at −20° C., to providecompound 8.

OTHER EMBODIMENTS

All publications and patents referred to in this disclosure areincorporated herein by reference to the same extent as if eachindividual publication or patent application were specifically andindividually indicated to be incorporated by reference. Should themeaning of the terms in any of the patents or publications incorporatedby reference conflict with the meaning of the terms used in thisdisclosure, the meaning of the terms defined in this disclosure isintended to be controlling.

The foregoing discussion discloses and describes exemplary embodimentsof this disclosure. One skilled in the art will readily recognize, fromsuch discussion and from the accompanying claims, that various changes,modifications, and variations can be made therein without departing fromthe spirit and scope of this disclosure as defined in the followingclaims.

1. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (I):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof, wherein: X^(a) is selected from F, Cl, Br, I, and —OSO₂R;R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionallysubstituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro; andX^(c) is selected from F, Cl, Br, and I.
 2. The method of claim 1,wherein the conversion of the compound of Formula (I), or a saltthereof, into Compound I, or a pharmaceutically acceptable salt thereof,comprises the steps of: 1) combining the compound of Formula (I), or asalt thereof, with at least one first base to produce a compound ofFormula (II):

or a salt thereof; and 2) combining the compound of Formula (II), or asalt thereof, with compound 1:

or a salt thereof, and at least one second base to produce Compound I,or a pharmaceutically acceptable salt thereof, wherein in the compoundof Formula (II), or a salt thereof: X^(a) is selected from F, Cl, Br, I,and —OSO₂R; and R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, andaryl optionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo,or nitro.
 3. The method of claim 1, wherein the conversion of thecompound of Formula (I), or a salt thereof, into Compound I, or apharmaceutically acceptable salt thereof, comprises combining thecompound of Formula (I), or a salt thereof, with compound 1:

or a salt thereof, and at least one third base to produce Compound I, ora pharmaceutically acceptable salt thereof, wherein in the compound ofFormula (I), or a salt thereof: X^(a) is selected from F, Cl, Br, I, and—OSO₂R; R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryloptionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, ornitro; and X^(c) is selected from F, Cl, Br, and I.
 4. The method ofclaim 1, wherein the compound of Formula (I):

or a salt thereof, is prepared by converting a compound of Formula(III):

or a salt thereof, into the compound of Formula (I), or a salt thereof,wherein in the compound of Formula (III), or a salt thereof: X^(a) isselected from F, Cl, Br, I, and —OSO₂R; R is selected from —C₁₋₁₀ alkyl,—C₁₋₁₀ haloalkyl, and aryl optionally substituted with —C₁₋₁₀ alkyl,—C₁₋₁₀ haloalkyl, halo, or nitro; X^(c) is selected from F, Cl, Br, andI; and wherein: R¹ is hydrogen and R² is a monovalent nitrogenprotecting group; R¹ and R² are independently selected from monovalentnitrogen protecting groups; or R¹ and R², together with the atoms towhich they are attached, form a nitrogen protecting group.
 5. The methodof claim 4, wherein the compound of Formula (III):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (III), or a saltthereof, wherein: X^(a) is selected from F, Cl, Br, I, and —OSO₂R; R isselected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionallysubstituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro X^(b) isselected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I; and wherein: R¹ is hydrogen andR² is a monovalent nitrogen protecting group; R¹ and R² areindependently selected from monovalent nitrogen protecting groups; or R¹and R², together with the atoms to which they are attached, form anitrogen protecting group.
 6. The method of claim 5, wherein thecompound of Formula (IV):

or a salt thereof, is prepared by converting a compound of Formula (VI):

or a salt thereof, into the compound of Formula (IV), or a salt thereof,wherein in the compound of Formula (VI), or a salt thereof: X^(a) isselected from F, Cl, Br, I, and —OSO₂R; and R is selected from —C₁₋₁₀alkyl, —C₁₋₁₀ haloalkyl, and aryl optionally substituted with —C₁₋₁₀alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro.
 7. The method of claim 6,wherein the compound of Formula (VI):

or a salt thereof, is prepared by combining compound 2:

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (VI), or a saltthereof, wherein in the compound of Formula (VII), or a salt thereof:X^(a) is selected from F, Cl, Br, I, and —OSO₂R; R is selected from—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionally substituted with—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro; and X^(d) is selectedfrom F, Cl, Br, and I.
 8. The method of claim 7, wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.
 9. The method ofclaim 8, wherein compound 3:

or a salt thereof, is prepared by converting compound 4:

or a salt thereof, into compound 3, or a salt thereof.
 10. The method ofclaim 9, wherein compound 4:

or a salt thereof, is prepared by chiral resolution of compound (±)-4:

or a salt thereof.
 11. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting acompound of Formula (VIII):

or a salt thereof, into Compound I, or a pharmaceutically acceptablesalt thereof, wherein in the compound of Formula (VIII), or a saltthereof, X^(c) is selected from F, Cl, Br, and I.
 12. The method ofclaim 11, wherein the compound of Formula (VIII):

or a salt thereof, is prepared by converting a compound of Formula (IX):

or a salt thereof, into the compound of Formula (VIII), or a saltthereof, wherein in the compound of Formula (IX), or a salt thereof:X^(c) is selected from F, Cl, Br, and I; and wherein: R¹ is hydrogen andR² is a monovalent nitrogen protecting group; R¹ and R² areindependently selected from monovalent nitrogen protecting groups; or R¹and R², together with the atoms to which they are attached, form anitrogen protecting group.
 13. The method of claim 12, wherein thecompound of Formula (IX):

or a salt thereof, is prepared by combining a compound of Formula (X):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (IX), or a saltthereof, wherein in the compound of Formula (X), or a salt thereof: R¹is hydrogen and R² is a monovalent nitrogen protecting group; R¹ and R²are independently selected from monovalent nitrogen protecting groups;or R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and wherein in the compound of Formula (V),or a salt thereof: X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I.
 14. The method of claim 13,wherein the compound of Formula (X):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with compound 1:

or a salt thereof, to produce the compound of Formula (X), or a saltthereof, wherein in the compound of Formula (IV), or a salt thereof:X^(a) is selected from F, Cl, Br, I, and —OSO₂R; R is selected from—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionally substituted with—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro; and wherein: R¹ ishydrogen and R² is a monovalent nitrogen protecting group; R¹ and R² areindependently selected from monovalent nitrogen protecting groups; or R¹and R², together with the atoms to which they are attached, form anitrogen protecting group.
 15. The method of claim 14, wherein thecompound of Formula (IV):

or a salt thereof, is prepared by combining a compound of Formula (XI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (IV), or a saltthereof, wherein in the compound of Formula (XI), or a salt thereof: R¹is hydrogen and R² is a monovalent nitrogen protecting group; R¹ and R²are independently selected from monovalent nitrogen protecting groups;or R¹ and R², together with the atoms to which they are attached, form anitrogen protecting group; and wherein in the compound of Formula (VII),or a salt thereof: X^(a) is selected from F, Cl, Br, I, and —OSO₂R; R isselected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionallysubstituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro; andX^(d) is selected from F, Cl, Br, and I.
 16. The method of claim 15,wherein the compound of Formula (XI):

or a salt thereof, is prepared by converting a compound of Formula(XII):

or a salt thereof, into the compound of Formula (XI), or a salt thereof,wherein in the compound of Formula (XII), or a salt thereof, R³ is amonovalent nitrogen protecting group.
 17. The method of claim 16,wherein the compound of Formula (XII):

or a salt thereof, is prepared by converting the compound of Formula(XV):

or a salt thereof, into the compound of Formula (XII), or a saltthereof, wherein in the compound of Formula (XV), or a salt thereof, R³is a monovalent nitrogen protecting group.
 18. The method of claim 17,wherein the conversion of the compound of Formula (XV), or a saltthereof, into the compound of Formula (XII), or a salt thereof,comprises the steps of: 1) converting the compound of Formula (XV):

or a salt thereof, into the compound of Formula (XIV):

or a salt thereof; 2) converting the compound of Formula (XIV), or asalt thereof, into the compound of Formula (XIII):

or a salt thereof; and 3) converting the compound of Formula (XIII), ora salt thereof, into the compound of Formula (XII), or a salt thereof,wherein in the compounds of Formulae (XIII)-(XV), or a salt thereof, R³is a monovalent nitrogen protecting group; and wherein in the compoundof Formula (XIV), or a salt thereof: R⁴ is —SO₂R; and R is selected from—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryl optionally substituted with—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, or nitro.
 19. The method of claim18, wherein the compound of Formula (XV):

or a salt thereof, is prepared by converting compound 2:

or a salt thereof, into the compound of Formula (XV), or a salt thereof.20. The method of claim 19, wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.
 21. The method ofclaim 20, wherein compound 3:

or a salt thereof, is prepared by chiral resolution of compound (±)-3:

or a salt thereof.
 22. The method of claim 21, wherein compound (±)-3:

or a salt thereof, is prepared by converting compound (±)-4:

or a salt thereof, into compound (±)-3, or a salt thereof.
 23. Themethod of claim 22, wherein compound (±)-4:

or a salt thereof, is prepared by combining compound 5:

or a salt thereof, with 2-nitropropane to produce compound (±)-4, or asalt thereof.
 24. The method of claim 2, wherein compound 1:

or a salt thereof, is prepared by converting compound 6:

or a salt thereof, into compound 1, or a salt thereof.
 25. The method ofclaim 24, wherein compound 6:

or a salt thereof, is prepared by converting compound 7:

or a salt thereof, into compound 6, or a salt thereof.
 26. The method ofclaim 25, wherein compound 7:

or a salt thereof, is prepared by combining compound 8:

or a salt thereof, with compound 9:

or a salt thereof, to produce compound 7, or a salt thereof.
 27. Themethod of claim 26, wherein compound 8:

or a salt thereof, is prepared by converting compound 10:

or a salt thereof, into compound 8, or a salt thereof.
 28. The method ofclaim 27, wherein compound 10:

or a salt thereof, is prepared by converting compound 11:

or a salt thereof, into compound 10, or a salt thereof.
 29. The methodof claim 28, wherein compound 11:

or a salt thereof, is prepared by converting compound 12:

or a salt thereof, into compound 11, or a salt thereof.
 30. The methodof claim 29, wherein compound 12:

or a salt thereof, is prepared by converting compound 13:

or a salt thereof, into compound 12, or a salt thereof.
 31. The methodof claim 30, wherein compound 13:

or a salt thereof, is prepared by converting compound 14:

or a salt thereof, into compound 13, or a salt thereof.
 32. The methodof claim 31, wherein compound 14:

or a salt thereof, is prepared by converting compound 15:

or a salt thereof, into compound 14, or a salt thereof.
 33. The methodof claim 32, wherein compound 15:

or a salt thereof, is prepared by converting compound 16:

or a salt thereof, into compound 15, or a salt thereof.
 34. The methodof claim 33, wherein compound 16:

or a salt thereof, is prepared by converting compound 17:

or a salt thereof, into compound 16, or a salt thereof.
 35. The methodof claim 34, wherein compound 17:

or a salt thereof, is prepared by converting compound 18:

or a salt thereof, into compound 17, or a salt thereof.
 36. The methodof claim 35, wherein compound 18:

or a salt thereof, is prepared by converting compound 19:

or a salt thereof, into compound 18, or a salt thereof.
 37. A compoundselected from:

and salts thereof, wherein: X^(a) is selected from F, Cl, Br, I, and—OSO₂R; R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryloptionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, ornitro; X^(b) is selected from Cl, F, —OC₆F₅,

X^(c) is selected from F, Cl, Br, and I; X^(d) is selected from F, Cl,Br, and I; R³ is a monovalent nitrogen protecting group; R⁴ is —SO₂R;and R is selected from —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and aryloptionally substituted with —C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, halo, ornitro; and wherein: R¹ is hydrogen and R² is a monovalent nitrogenprotecting group; R¹ and R² are independently selected from monovalentnitrogen protecting groups; or R¹ and R², together with the atoms towhich they are attached, form a nitrogen protecting group; and whereinthe compound is not:

or a salt thereof.